Irak degraders and uses thereof

ABSTRACT

The present invention provides compounds, compositions thereof, and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.17/650,545, filed Feb. 10, 2022, which is a continuation of U.S. patentapplication Ser. No. 17/073,019, filed Oct. 16, 2020, now U.S. Pat. No.11,318,205, which is a continuation of U.S. patent application Ser. No.16/230,792, filed Dec. 21, 2018, now U.S. Pat. No. 10,874,743, andclaims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Appl.No. 62/610,397, filed Dec. 26, 2017, U.S. Provisional Appl. No.62/653,178, filed Apr. 5, 2018, U.S. Provisional Appl. No. 62/694,955,filed Jul. 6, 2018, and U.S. Provisional Appl. No. 62/712,377, filedJul. 31, 2018, the content of each of which is herein incorporated byreference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds and methods useful for themodulation of one or more interleukin-1 receptor-associated kinases(“IRAK”) via ubiquitination and/or degradation by compounds according tothe present invention. The invention also provides pharmaceuticallyacceptable compositions comprising compounds of the present inventionand methods of using said compositions in the treatment of variousdisorders.

BACKGROUND OF THE INVENTION

Ubiquitin-Proteasome Pathway (UPP) is a critical pathway that regulateskey regulator proteins and degrades misfolded or abnormal proteins. UPPis central to multiple cellular processes, and if defective orimbalanced, it leads to pathogenesis of a variety of diseases. Thecovalent attachment of ubiquitin to specific protein substrates isachieved through the action of E3 ubiquitin ligases.

There are over 600 E3 ubiquitin ligases which facilitate theubiquitination of different proteins in vivo, which can be divided intofour families: HECT-domain E3s, U-box E3s, monomeric RING E3s andmulti-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487)titled “Genome-wide and functional annotation of human E3 ubiquitinligases identifies MULAN, a mitochondrial E3 that regulates theorganelle's dynamics and signaling.”; Berndsen et al. (Nat. Struct. Mol.Biol., 2014, 21, 301-307) titled “New insights into ubiquitin E3 ligasemechanism”; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434)titled “RING domain E3 ubiquitin ligases.”; Spratt et al. (Biochem.2014, 458, 421-437) titled “RBR E3 ubiquitin ligases: new structures,new insights, new questions.”; and Wang et al. (Nat. Rev. Cancer., 2014,14, 233-347) titled “Roles of F-box proteins in cancer.”

UPP plays a key role in the degradation of short-lived and regulatoryproteins important in a variety of basic cellular processes, includingregulation of the cell cycle, modulation of cell surface receptors andion channels, and antigen presentation. The pathway has been implicatedin several forms of malignancy, in the pathogenesis of several geneticdiseases (including cystic fibrosis, Angelman's syndrome, and Liddlesyndrome), in immune surveillance/viral pathogenesis, and in thepathology of muscle wasting. Many diseases are associated with anabnormal UPP and negatively affect cell cycle and division, the cellularresponse to stress and to extracellular modulators, morphogenesis ofneuronal networks, modulation of cell surface receptors, ion channels,the secretory pathway, DNA repair and biogenesis of organelles.

Aberrations in the process have recently been implicated in thepathogenesis of several diseases, both inherited and acquired. Thesediseases fall into two major groups: (a) those that result from loss offunction with the resultant stabilization of certain proteins, and (b)those that result from gain of function, i.e. abnormal or accelerateddegradation of the protein target.

The UPP is used to induce selective protein degradation, including useof fusion proteins to artificially ubiquitinate target proteins andsynthetic small-molecule probes to induce proteasome-dependentdegradation. Bifunctional compounds composed of a target protein-bindingligand and an E3 ubiquitin ligase ligand, induced proteasome-mediateddegradation of selected proteins via their recruitment to E3 ubiquitinligase and subsequent ubiquitination. These drug-like molecules offerthe possibility of temporal control over protein expression. Suchcompounds are capable of inducing the inactivation of a protein ofinterest upon addition to cells or administration to an animal or human,and could be useful as biochemical reagents and lead to a new paradigmfor the treatment of diseases by removing pathogenic or oncogenicproteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; SchnneklothJS Jr., Chembiochem, 2005, 6(1):40-46).

An ongoing need exists in the art for effective treatments for disease,especially hyperplasias and cancers, such as multiple myeloma. However,non-specific effects, and the inability to target and modulate certainclasses of proteins altogether, such as transcription factors, remain asobstacles to the development of effective anti-cancer agents. As such,small molecule therapeutic agents that leverage E3 ligase mediatedprotein degradation to target cancer-associated proteins such asinterleukin-1 receptor-associated kinases (“IRAK”) hold promise astherapeutic agents. Accordingly, there remains a need to findbifunctional compounds that are IRAK degraders useful as therapeuticagents.

SUMMARY OF THE INVENTION

The present application relates novel bifunctional compounds, whichfunction to recruit IRAK kinases to E3 Ubiquitin Ligase for degradation,and methods of preparation and uses thereof. In particular, the presentdisclosure provides bifunctional compounds, which find utility asmodulators of targeted ubiquitination of IRAK kinases, which are thendegraded and/or otherwise inhibited by the bifunctional compounds asdescribed herein. An advantage of the compounds provided herein is thata broad range of pharmacological activities is possible, consistent withthe degradation/inhibition of IRAK kinases. In addition, the descriptionprovides methods of using an effective amount of the compounds asdescribed herein for the treatment or amelioration of a diseasecondition, such as cancer, e.g., multiple myeloma.

The present application further relates to targeted degradation of IRAKkinases through the use of bifunctional molecules, includingbifunctional molecules that link a cereblon-binding moiety to a ligandthat binds IRAK kinases.

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are effective asdegraders of IRAK kinases. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable isas defined and described herein.

Compounds of the present invention, and pharmaceutically acceptablecompositions thereof, are useful for treating a variety of diseases,disorders or conditions, associated with regulation of signalingpathways implicating IRAK kinases. Such diseases, disorders, orconditions include those described herein.

Compounds provided by this invention are also useful for the study ofIRAK enzymes in biological and pathological phenomena; the study ofintracellular signal transduction pathways occurring in bodily tissues;and the comparative evaluation of new IRAK inhibitors or IRAK degradersor other regulators of kinases, signaling pathways, and cytokine levelsin vitro or in vivo.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the ternary complex formation (as a percentage of totalIRAK4) mediated by I-127.

FIG. 2 depicts the ternary complex formation (as a percentage of totalIRAK4) mediated by I-135.

FIG. 3 depicts ABL-DLBCL cell viability assay results for I-127.

FIG. 4 depicts human PBMC cytokine release assays results, R848 (TLR7/8)activation, for I-127.

FIG. 5 depicts human PBMC cytokine release assays results, LPS (TLR4)stimulation, for I-127.

FIG. 6 depicts in vivo degradation in Sprague Dawley rat splenocytes forI-171.

FIG. 7 depicts the plasma and brain concentration versus time profilefor I-210 after 3 mg/kg IV and 10 mg/kg PO in Sprague Dawley rat.

FIG. 8 depicts the plasma concentration versus time profile for I-210after 2 mg/kg IV, 30 mg/kg PO and 30 mg/kg SC in CD1 mouse.

FIG. 9 depicts the mean plasma concentration of I-127 after IV, PO andSC dosing.

FIG. 10 depicts the plasma concentration versus time profile for I-172after 2 mg/kg IV and 30 mg/kg SC in CD1 mouse.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description ofCertain Embodiments of the Invention

Compounds of the present invention, and compositions thereof, are usefulas degraders and/or inhibitors of one or more IRAK protein kinases. Insome embodiments, a provided compound degrades and/or inhibitsIRAK-1/2/3/4.

In certain embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   IRAK is an IRAK binding moiety capable of binding to one or more        of IRAK-1, -2, -3, or -4;    -   L is a bivalent moiety that connects IRAK to LBM; and    -   LBM is a ligase binding moiety.

2. Compounds and Definitions

Compounds of the present invention include those described generallyherein, and are further illustrated by the classes, subclasses, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated. For purposes of this invention,the chemical elements are identified in accordance with the PeriodicTable of the Elements, CAS version, Handbook of Chemistry and Physics,75^(th) Ed. Additionally, general principles of organic chemistry aredescribed in “Organic Chemistry”, Thomas Sorrell, University ScienceBooks, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th)Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001,the entire contents of which are hereby incorporated by reference.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-6 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-5aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-3 aliphatic carbon atoms, and in yet other embodiments,aliphatic groups contain 1-2 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₆ hydrocarbon that is completely saturated or thatcontains one or more units of unsaturation, but which is not aromatic,that has a single point of attachment to the rest of the molecule.Suitable aliphatic groups include, but are not limited to, linear orbranched, substituted or unsubstituted alkyl, alkenyl, alkynyl groupsand hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or(cycloalkyl)alkenyl.

As used herein, the term “bridged bicyclic” refers to any bicyclic ringsystem, i.e. carbocyclic or heterocyclic, saturated or partiallyunsaturated, having at least one bridge. As defined by IUPAC, a “bridge”is an unbranched chain of atoms or an atom or a valence bond connectingtwo bridgeheads, where a “bridgehead” is any skeletal atom of the ringsystem which is bonded to three or more skeletal atoms (excludinghydrogen). In some embodiments, a bridged bicyclic group has 7-12 ringmembers and 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Such bridged bicyclic groups are well known in theart and include those groups set forth below where each group isattached to the rest of the molecule at any substitutable carbon ornitrogen atom. Unless otherwise specified, a bridged bicyclic group isoptionally substituted with one or more substituents as set forth foraliphatic groups. Additionally or alternatively, any substitutablenitrogen of a bridged bicyclic group is optionally substituted.Exemplary bridged bicyclics include:

The term “lower alkyl” refers to a C₁₋₄ straight or branched alkylgroup. Exemplary lower alkyl groups are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, and tert-butyl.

The term “lower haloalkyl” refers to a C₁₋₄ straight or branched alkylgroup that is substituted with one or more halogen atoms.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

As used herein, the term “bivalent C₁₋₈ (or C₁₋₆) saturated orunsaturated, straight or branched, hydrocarbon chain”, refers tobivalent alkylene, alkenylene, and alkynylene chains that are straightor branched as defined herein.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

The term “alkenylene” refers to a bivalent alkenyl group. A substitutedalkenylene chain is a polymethylene group containing at least one doublebond in which one or more hydrogen atoms are replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group.

As used herein, the term “cyclopropylenyl” refers to a bivalentcyclopropyl group of the following structure:

The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic orbicyclic ring systems having a total of five to fourteen ring members,wherein at least one ring in the system is aromatic and wherein eachring in the system contains 3 to 7 ring members. The term “aryl” may beused interchangeably with the term “aryl ring.” In certain embodimentsof the present invention, “aryl” refers to an aromatic ring system whichincludes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl andthe like, which may bear one or more substituents. Also included withinthe scope of the term “aryl,” as it is used herein, is a group in whichan aromatic ring is fused to one or more non-aromatic rings, such asindanyl, phthalimidyl, naphthimidyl, phenanthridinyl, ortetrahydronaphthyl, and the like.

The terms “heteroaryl” and “heteroar-,” used alone or as part of alarger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer togroups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms;having 6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group may be mono- or bicyclic. The term “heteroaryl” may beused interchangeably with the terms “heteroaryl ring,” “heteroarylgroup,” or “heteroaromatic,” any of which terms include rings that areoptionally substituted. The term “heteroaralkyl” refers to an alkylgroup substituted by a heteroaryl, wherein the alkyl and heteroarylportions independently are optionally substituted.

As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclicradical,” and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 7-membered monocyclic or 7-10-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, preferably one tofour, heteroatoms, as defined above. When used in reference to a ringatom of a heterocycle, the term “nitrogen” includes a substitutednitrogen. As an example, in a saturated or partially unsaturated ringhaving 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, thenitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as inpyrrolidinyl), or ⁺NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. Theterms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclicgroup,” “heterocyclic moiety,” and “heterocyclic radical,” are usedinterchangeably herein, and also include groups in which a heterocyclylring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings,such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, ortetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. Theterm “heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄R^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄ S(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences of Rt,taken together with their intervening atom(s) form an unsubstituted3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate,propionate, stearate, succinate, sulfate, tartrate, thiocyanate,p-toluenesulfonate, undecanoate, valerate salts, and the like.

Salts derived from appropriate bases include alkali metal, alkalineearth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. Representative alkali oralkaline earth metal salts include sodium, lithium, potassium, calcium,magnesium, and the like. Further pharmaceutically acceptable saltsinclude, when appropriate, nontoxic ammonium, quaternary ammonium, andamine cations formed using counterions such as halide, hydroxide,carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and arylsulfonate.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention

As used herein, the term “inhibitor” is defined as a compound that bindsto and/or inhibits an IRAK kinase with measurable affinity. In certainembodiments, an inhibitor has an IC₅₀ and/or binding constant of lessthan about 50 μM, less than about 1 μM, less than about 500 nM, lessthan about 100 nM, less than about 10 nM, or less than about 1 nM.

As used herein, the term “degrader” is defined as a heterobifunctionalcompound that binds to and/or inhibits both an IRAK kinase and an E3ligase with measurable affinity resulting in the ubiqitination andsubsequent degradation of the IRAK kinase. In certain embodiments, adegrader has an DC₅₀ of less than about 50 μM, less than about 1 μM,less than about 500 nM, less than about 100 nM, less than about 10 nM,or less than about 1 nM.

A compound of the present invention may be tethered to a detectablemoiety. It will be appreciated that such compounds are useful as imagingagents. One of ordinary skill in the art will recognize that adetectable moiety may be attached to a provided compound via a suitablesubstituent. As used herein, the term “suitable substituent” refers to amoiety that is capable of covalent attachment to a detectable moiety.Such moieties are well known to one of ordinary skill in the art andinclude groups containing, e.g., a carboxylate moiety, an amino moiety,a thiol moiety, or a hydroxyl moiety, to name but a few. It will beappreciated that such moieties may be directly attached to a providedcompound or via a tethering group, such as a bivalent saturated orunsaturated hydrocarbon chain. In some embodiments, such moieties may beattached via click chemistry. In some embodiments, such moieties may beattached via a 1,3-cycloaddition of an azide with an alkyne, optionallyin the presence of a copper catalyst. Methods of using click chemistryare known in the art and include those described by Rostovtsev et al.,Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., BioconjugateChem., 2006, 17, 52-57.

As used herein, the term “detectable moiety” is used interchangeablywith the term “label” and relates to any moiety capable of beingdetected, e.g., primary labels and secondary labels. Primary labels,such as radioisotopes (e.g., tritium, ³²P, ³³P, ³⁵S, or ¹⁴C), mass-tags,and fluorescent labels are signal generating reporter groups which canbe detected without further modifications. Detectable moieties alsoinclude luminescent and phosphorescent groups.

The term “secondary label” as used herein refers to moieties such asbiotin and various protein antigens that require the presence of asecond intermediate for production of a detectable signal. For biotin,the secondary intermediate may include streptavidin-enzyme conjugates.For antigen labels, secondary intermediates may include antibody-enzymeconjugates. Some fluorescent groups act as secondary labels because theytransfer energy to another group in the process of nonradiativefluorescent resonance energy transfer (FRET), and the second groupproduces the detected signal.

The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” asused herein refer to moieties that absorb light energy at a definedexcitation wavelength and emit light energy at a different wavelength.Examples of fluorescent labels include, but are not limited to: AlexaFluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, AlexaFluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, AlexaFluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL,BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568,BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY650/665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue,Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5),Dansyl, Dapoxyl, Dialkylaminocoumarin,4′,5′-Dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin,Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800),JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin,Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, RhodamineGreen, Rhodamine Red, Rhodol Green,2′,4′,5′,7′-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR),Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

The term “mass-tag” as used herein refers to any moiety that is capableof being uniquely detected by virtue of its mass using mass spectrometry(MS) detection techniques. Examples of mass-tags include electrophorerelease tags such asN-[3-[4′-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecoticAcid, 4′-[2,3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and their derivatives. The synthesis and utility of thesemass-tags is described in U.S. Pat. Nos. 4,650,750, 4,709,016,5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270.Other examples of mass-tags include, but are not limited to,nucleotides, dideoxynucleotides, oligonucleotides of varying length andbase composition, oligopeptides, oligosaccharides, and other syntheticpolymers of varying length and monomer composition. A large variety oforganic molecules, both neutral and charged (biomolecules or syntheticcompounds) of an appropriate mass range (100-2000 Daltons) may also beused as mass-tags.

The terms “measurable affinity” and “measurably inhibit,” as usedherein, means a measurable change in an IRAK protein kinase activitybetween a sample comprising a compound of the present invention, orcomposition thereof, and an IRAK protein kinase, and an equivalentsample comprising an IRAK protein kinase, in the absence of saidcompound, or composition thereof.

3. Description of Exemplary Embodiments

As described above, in certain embodiments, the present inventionprovides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   IRAK is an IRAK binding moiety capable of binding to one or more        of IRAK-1, -2, -3, or -4;    -   L is a bivalent moiety that connects IRAK to LBM; and    -   LBM is a ligase binding moiety.

In some embodiments, the present invention provides a compound offormula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   IRAK is an IRAK-4 binding moiety;    -   L is a bivalent moiety that connects IRAK to LBM; and    -   LBM is a cereblon ligase binding moiety.

In some embodiments, LBM is an E3 ligase ligand. Such E3 ligase ligandsare well known to one of ordinary skill in the art and include thosedescribed in M. Toure, C. M. Crews, Angew. Chem. Int. Ed. 2016, 55,1966, T. Uehara et al. Nature Chemical Biology 2017, 13, 675, WO2017/176708, US 2017/0281784, WO 2017/161119, WO 2017/176957, WO2017/176958, WO 2015/160845, US 2015/0291562, WO 2016/197032, WO2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684, WO2013/106643, US 2014/0356322, WO 2002/020740, US 2002/0068063, WO2012/078559, US 2014/0302523, WO 2012/003281, US 2013/0190340, US2016/0022642, WO 2014/063061, US 2015/0274738, WO 2016/118666, US2016/0214972, WO 2016/149668, US 2016/0272639, WO 2016/169989, US2018/0118733, WO 2016/197114, US 2018/0147202, WO 2017/011371, US2017/0008904, WO 2017/011590, US 2017/0037004, WO 2017/079267, US2017/0121321, WO 2017/117473, WO 2017/117474, WO 2013/106646, WO2014/108452, WO 2017/197036, WO 2017/197046, WO 2017/197051, WO2017/197055, and WO 2017/197056 each of, the entirety of each of whichis herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-a-1, I-a-2, I-a-3, I-a-4, I-a-5,I-a-6, I-a-7, I-a-8 I-a-9 or I-a-10 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables

X, X₁, X₂, Y, R₁, R₃, R₃′, R₄, R₅, t, m and n is as defined anddescribed in WO 2017/007612 and US 2018/0134684, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-a′-1, I-a′-2, I-a′-3, I-a′-4,I-a′-5, I-a′-6, I-a′-7, I-a′-8, I-a′-9, or I-a′-10 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables

X, X₁, X₂, Y, R₁, R₃, R₃′, R₄, R₅, t, m and n is as defined anddescribed in WO 2017/007612 and US 2018/0134684, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-a″-1, I-a″-2, I-a″-3, I-a″-4,I-a″-5, I-a″-6, I-a″-7, I-a″-8, I-a″-9, or I-a′-10 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables

X, X₁, X₂, Y, R₁, R₃, R₃′, R₄, R₅, t, m and n is as defined anddescribed in WO 2017/007612 and US 2018/0134684, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety

thereby forming a compound of formula I-b-1, I-b-2, I-b-3, I-b-4, orI-b-5 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R^(1′), R^(2′), R^(3′), X, and X′ is as defined anddescribed in WO 2013/106643 and US 2014/0356322, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-c:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein

-   -   Ring B is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-2 heteroatoms independently selected from nitrogen,        oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-c′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein

-   -   Ring B is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-2 heteroatoms independently selected from boron,        nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl        with 1-3 heteroatoms independently selected from nitrogen,        oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, the compound of formula I-c′ above is provided as acompound of formula I-c″ or formula I-c′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, L, R¹, R², X¹, X², X³, and m is as defined        above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-d:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring A and        Ring B is connected to

and

-   -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-d′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, deuterium, —R, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring A and        Ring B is connected to

and

-   -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, the compound of formula I-d′ above is provided as acompound of formula I-d″ or formula I-d′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, Ring B, L, R¹, R², R³, X¹, X², X³, m, and        p is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-e:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-e′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, the compound of formula I-e′ above is provided as acompound of formula I-e″ or formula I-e′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, Ring B, L, R¹, R², R³, X¹, X², X³, p, and        m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety

thereby forming a compound of formula I-f-1, I-f-2, I-f-3, I-f-4, I-f-5or I-f-6 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R^(1′), R^(2′), R^(3′), R₅, R₆, R₇, R₉, R₁₀, R₁₁, R₁₄,R₁₅, R₁₆, R₁₇, R₂₃, R₂₅, E, G, M, X, X′, Y, Z₁, Z₂, Z₃, Z₄, and o is asdefined and described in WO 2016/149668 and US 2016/0272639, theentirety of each of which is herein incorporated by reference.

As used herein, depiction of brackets around any LBM

means that the

moiety is covalently attached to said LBM at any available modifiablecarbon, nitrogen, oxygen, or sulfur atom. For purposes of clarity and byway of example, such available modifiable carbon, nitrogen, oxygen, orsulfur atoms in the following LBM compound structure are depicted below,wherein each wavy bond defines the point of attachment to said

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety

thereby forming a compound of formula I-g-1, I-g-2, or I-g-3respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R^(p), R₉, R₁₀, R₁₁, R_(14a), R_(14b), R₁₅, R₁₆, W³, W⁴,W⁵, X¹, X², and o is as defined and described in WO 2016/118666 and US2016/0214972, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-h-1, I-h-2, I-h-3, I-h-4, I-h-5,or I-h-6 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein

-   -   W is independently selected from the group CH₂, CHR, C═O, SO₂,        NH, and N-alkyl;    -   X is independently selected from the group O, S and H₂;    -   Y is independently selected from the group NH, N-alkyl, N-aryl,        N-hetaryl, N-cycloalkyl, N-heterocyclyl, O, and S;    -   Z is independently selected from the group O, and S or H₂,        except that both X and Z cannot be H₂;    -   G and G′ are independently selected from the group H, alkyl, OH,        CH₂-heterocyclyl optionally substituted with R′, and benzyl        optionally substituted with R′;    -   Q1-Q4 represent a carbon C substituted with a group        independently selected from R′, N or N-oxide;    -   A is independently selected from the group H, alkyl, cycloalkyl,        Cl and F;    -   R comprises, but is not limited to: —CONR′R″, —OR′, —NR′R″,        —SR′, —SO₂R′, —SO₂NR′R″, —CR′R″—, —CR′NR′R″—, -aryl, -hetaryl,        -alkyl, -cycloalkyl, -heterocyclyl, —P(O)(OR′)R″, —P(O)R′R″,        —OP(O)(OR′)R″, —OP(O)R′R″, —Cl, —F, —Br, —I, —CF₃, —CN,        —NR′SO₂NR′R″, —NR′CONR′R″, —CONR′COR″, —NR′C(═N—CN)NR′R″,        —C(═N—CN)NR′R″, —NR′C(═N—CN)R″, —NR′C(═C—NO₂)NR′R″, —SO₂NR′COR″,        —NO₂, —CO₂R′, —C(C═N—OR′)R″, —CR′═CR′R″, —CCR′,        —S(C═O)(C═N—R′)R″, —SF₅ and —OCF₃;    -   R′ and R″ are independently selected from a bond, H, alkyl,        cycloalkyl, aryl, hetaryl, heterocyclyl;    -   n is an integer from 1-4;    -   represents a bond that may be stereospecific ((R) or (S)) or        non-stereospecific; and    -   R_(n) comprises 1-4 independent functional groups or atoms;        as defined and described in WO 2016/197114 and US 2018/0147202,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a MDM2 (i.e. human double minute 2 or HDM2) E3ligase binding moiety

thereby forming a compound of formula I-i-1, I-i-2, I-i-3, I-i-4, I-i-5,I-i-6, I-i-7, I-i-8, I-i-9, I-i-10, I-i-11, I-i-12, I-i-13, I-i-14,I-i-15, I-i-16, I-i-17, or I-i-18 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃,R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, R₂₇,R₂₈, R_(1′), R_(2′), R_(3′), R_(4′), R_(5′), R_(6′), R_(7′), R_(8′),R_(9′), R_(10′), R_(11′), R_(12′), R_(1″), A, A′, A″, X, Y, and Z is asdefined and described in WO 2017/011371 and US 2017/0008904, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase bindingmoiety selected from the group consisting of

thereby forming a compound of formula I-j-1, I-j-2, I-j-3, I-j-4, I-j-5,I-j-6, or I-j-7 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        IRAK are as defined above and described in embodiments herein,        and wherein    -   A¹ is selected from the group consisting of —C(R^(16a))═ and        —N—;    -   A² is selected from the group consisting of —C(R^(16b))═ and        —N—;    -   A³ is selected from the group consisting of —C(R^(16c))═ and        —N—;    -   G is selected from the group consisting of —C(R^(16d))═ and —N—;    -   Z is selected from the group consisting of —CH₂ and —C(═O)—;    -   R⁵ is selected from the group consisting of hydrogen, methyl,        and fluoro;    -   R^(16a) is selected from the group consisting of hydrogen, halo,        and C₁₋₄ alkyl;    -   R^(16b) is selected from the group consisting of hydrogen, halo,        and C₁₋₄ alkyl;    -   R^(16c) is selected from the group consisting of hydrogen, halo,        and C₁₋₄ alkyl; and    -   R^(16d) is selected from the group consisting of hydrogen, halo,        and C₁₋₄ alkyl;        as defined and described in WO 2017/176958, the entirety of        which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase bindingmoiety selected from the group consisting of

thereby forming a compound of formula I-j′-1, I-j″-1, I-j′-2, I-j″-2,I-j′-3, I-j″-3, I-j′-4, I-j″-4, I-j′-7 or I-j″-7 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables A¹, A², A³, R⁵, G and Z is as defined and described in WO2017/176958, the entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an IAP E3 ubiquitin ligase binding moiety

thereby forming a compound of formula I-k-1, I-k-2, I-k-3, or I-k-4respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, R⁴, R⁵, R⁶, and R⁷, is as defined anddescribed in WO 2017/011590 and US 2017/0037004, the entirety of each ofwhich is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an IAP E3 ubiquitin ligase binding moiety

thereby forming a compound of formula I-k′-1, I-k′-2, I-k′-3, or I-k′-4respectively:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R³, R⁴, R⁵, R⁶, and R′, is as defined and described inWO 2017/011590 and US 2017/0037004, the entirety of each of which isherein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

Thereby forming a compound of formula I-1:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein

-   -   Ring B is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-2 heteroatoms independently selected from nitrogen,        oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a bivalent, saturated or unsaturated,        straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6        methylene units of L are independently replaced by -Cy-, —O—,        —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—,        —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   -   each -Cy- is independently an optionally substituted bivalent        ring selected from phenylenyl, an 8-10 membered bicyclic        arylenyl, a 4-7 membered saturated or partially unsaturated        carbocyclylenyl, a 4-7 membered saturated or partially        unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic        saturated or partially unsaturated carbocyclylenyl, a 4-7        membered saturated or partially unsaturated heterocyclylenyl        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, a 4-7 membered saturated or partially        unsaturated spiro heterocyclylenyl having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, an        8-10 membered bicyclic saturated or partially unsaturated        heterocyclylenyl having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   m is 0, 1, 2, 3 or 4;    -   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(n) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(n) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

Thereby forming a compound of formula I-1′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein

-   -   Ring B is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-2 heteroatoms independently selected from nitrogen,        oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a bivalent, saturated or unsaturated,        straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6        methylene units of L are independently replaced by -Cy-, —O—,        —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—,        —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   -   each -Cy- is independently an optionally substituted bivalent        ring selected from phenylenyl, an 8-10 membered bicyclic        arylenyl, a 4-7 membered saturated or partially unsaturated        carbocyclylenyl, a 4-7 membered saturated or partially        unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic        saturated or partially unsaturated carbocyclylenyl, a 4-7        membered saturated or partially unsaturated heterocyclylenyl        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, a 4-7 membered saturated or partially        unsaturated spiro heterocyclylenyl having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, an        8-10 membered bicyclic saturated or partially unsaturated        heterocyclylenyl having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   m is 0, 1, 2, 3 or 4;    -   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

Where a point of attachment of —(R²)_(n) is depicted on Ring B, it isintended, and one of ordinary skill in the art would appreciate, thatthe point of attachment of —(R²)_(n) may be on Ring A and may also be atany available carbon or nitrogen atom on Ring A including the ring towhich Ring B is fused. Where —R² is attached to a nitrogen atom bound toR⁴ or R⁵, R⁴ or R⁵ is absent and —R² takes the place of the R⁴ or R⁵group. Where —R² is attached to a carbon atom bound to R³, R³ is absentand —R² takes the place of the R³ group.

In some embodiments, a compound of formula I-i′ above is provided as acompound of formula I-1″ or formula I-1′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, L, L¹, R¹, R², X, and m is as defined        above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

Thereby forming a compound of formula I-m:

or a pharmaceutically acceptable salt thereof, wherein, L and IRAK areas defined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a bivalent, saturated or unsaturated,        straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6        methylene units of L are independently replaced by -Cy-, —O—,        —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—,        —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   -   each -Cy- is independently an optionally substituted bivalent        ring selected from phenylenyl, an 8-10 membered bicyclic        arylenyl, a 4-7 membered saturated or partially unsaturated        carbocyclylenyl, a 4-7 membered saturated or partially        unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic        saturated or partially unsaturated carbocyclylenyl, a 4-7        membered saturated or partially unsaturated heterocyclylenyl        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, a 4-7 membered saturated or partially        unsaturated spiro heterocyclylenyl having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, an        8-10 membered bicyclic saturated or partially unsaturated        heterocyclylenyl having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring A and        Ring B is connected to

-   -   each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

Thereby forming a compound of formula I-m′:

or a pharmaceutically acceptable salt thereof, wherein, L and IRAK areas defined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a bivalent, saturated or unsaturated,        straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6        methylene units of L are independently replaced by -Cy-, —O—,        —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—,        —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   -   each -Cy- is independently an optionally substituted bivalent        ring selected from phenylenyl, an 8-10 membered bicyclic        arylenyl, a 4-7 membered saturated or partially unsaturated        carbocyclylenyl, a 4-7 membered saturated or partially        unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic        saturated or partially unsaturated carbocyclylenyl, a 4-7        membered saturated or partially unsaturated heterocyclylenyl        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, a 4-7 membered saturated or partially        unsaturated spiro heterocyclylenyl having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, an        8-10 membered bicyclic saturated or partially unsaturated        heterocyclylenyl having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring A and        Ring B is connected to

-   -   each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-m′ above is provided as acompound of formula I-m″ or formula I-m′″

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, Ring B, L, L¹, R¹, R², R³, X¹, p, and m is        as defined above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

Thereby forming a compound of formula I-n:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a bivalent, saturated or unsaturated,        straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6        methylene units of L are independently replaced by -Cy-, —O—,        —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—,        —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   -   each -Cy- is independently an optionally substituted bivalent        ring selected from phenylenyl, an 8-10 membered bicyclic        arylenyl, a 4-7 membered saturated or partially unsaturated        carbocyclylenyl, a 4-7 membered saturated or partially        unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic        saturated or partially unsaturated carbocyclylenyl, a 4-7        membered saturated or partially unsaturated heterocyclylenyl        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, a 4-7 membered saturated or partially        unsaturated spiro heterocyclylenyl having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, an        8-10 membered bicyclic saturated or partially unsaturated        heterocyclylenyl having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1;    -   each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

Thereby forming a compound of formula I-n′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   L¹ is a covalent bond or a bivalent, saturated or unsaturated,        straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6        methylene units of L are independently replaced by -Cy-, —O—,        —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—,        —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   -   each -Cy- is independently an optionally substituted bivalent        ring selected from phenylenyl, an 8-10 membered bicyclic        arylenyl, a 4-7 membered saturated or partially unsaturated        carbocyclylenyl, a 4-7 membered saturated or partially        unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic        saturated or partially unsaturated carbocyclylenyl, a 4-7        membered saturated or partially unsaturated heterocyclylenyl        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, a 4-7 membered saturated or partially        unsaturated spiro heterocyclylenyl having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, an        8-10 membered bicyclic saturated or partially unsaturated        heterocyclylenyl having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1;    -   each of q is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-n′ above is provided as acompound of formula I-n″ or formula I-n′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, Ring B, L, L¹, R¹, R², R³, X¹, p, and m is        as defined above.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-o:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        IRAK are as defined above and described in embodiments herein,        and wherein:    -   Ar is aryl, heteroaryl, cycloalkyl, or heterocyclyl;    -   L¹ is absent or a linker selected from the group consisting of        —SO₂, —SO₂R′; SO₂R′R″, —SO₂NR′R″; —SO₂NR′R″C(═O); —NR′SO₂R;        —R′SO₂NR′R′; —C(═O); —C(═O)R′; —OC(═O)R′; —C(═O)NR′R″;        —NR′C(═O)R″; —NR′C(═O)R″C(═O); —OR′; —NR′R″; —SR′; —N₃—C(═O)OR′;        —O(CR′R″)rC(O)R′; —O(CR′R″)rNR″C(═O)R′; —O(CR′R″)rNR″SO₂R′;        —OC(═O)NR′R; —NR′C(═O)OR″; and substituted or unsubstituted        C₁-C₆ aliphatic alkyl;    -   wherein R′, R″, and R′″ are individually selected from hydrogen;        substituted or unsubstituted alkyl; substituted or unsubstituted        alkenyl; substituted or unsubstituted ether; substituted or        unsubstituted cycloalkyl; substituted or unsubstituted        heterocyclyl; substituted or unsubstituted cycloalkenyl,        substituted or unsubstituted aryl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted arylalkyl, substituted        or unsubstituted heteroalkyl, substituted or unsubstituted        alkylheteroaryl, or substituted or unsubstituted amine; and r is        an integer from 1 to 6;    -   R¹, R², and R³ are individually selected from the group        consisting of hydrogen, halogen, hydroxyl, azide, alkoxyl,        sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,        carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonamido,        ketone, aldehyde, substituted or unsubstituted amine,        substituted or unsubstituted amide, nitro, ester, morpholino,        dioxolane, substituted or unsubstituted alkyl, substituted or        unsubstituted alkylhalide, substituted or unsubstituted aralkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkyl; substituted or        unsubstituted heterocyclyl; substituted or unsubstituted        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted alkylheteroaryl, and combinations thereof; or    -   wherein R¹ and R² combine to form a 5-7 membered heterocyclic        ring; and wherein when R¹ and R² combine to form a 5-7 membered        heterocyclic ring, Ar is optionally not fused to the 5-7        membered heterocyclic ring but is a substituent of the 5-7        membered heterocyclic ring;    -   R⁴ and R⁵ are individually selected from the group consisting of        hydrogen, halogen, hydroxyl, azide, ether, alkoxyl, sulfhydryl,        alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkylhalide, substituted or unsubstituted aralkyl, substituted        or unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted cycloalkyl, heterocyclyl, and        combinations thereof;    -   R⁸ is selected from the group consisting of hydrogen,        substituted or unsubstituted alkyl, substituted or unsubstituted        alkylhalide, substituted or unsubstituted aralkyl, substituted        or unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted cycloalkyl, heterocyclyl,        substituted or unsubstituted aryl, substituted or unsubstituted        alkylaryl, and combinations thereof; and    -   x is 0, 1, or 2; as described and defined in WO 2017/161119, the        entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-p:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and further wherein:

-   -   A is C, S; substituted of unsubstituted C₁-C₈ alkyl, or        combinations thereof;    -   R⁶ and R⁷ are individually ═O, hydrogen, C₁-C₈ alkyl, or R⁶ and        R⁷ combine to form ═O; and each of the variables Ar, R¹, R², R³,        R⁴, R⁵, R′, x, and the bond - - - is as described above and as        described and defined in WO 2017/161119, the entirety of each of        which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-q:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R′, A, x, and the bond - - -is as described above described and defined in WO 2017/161119, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-r:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables Ar, R¹, R², R³, R⁴, R⁵, R⁸, L, x, y, and the bond - - - isas described above and described and defined in WO 2017/161119, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-s:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   G comprises C, S, N, substituted of unsubstituted C₁-C₈ alkyl,        or combinations thereof; R³ is selected from the group        consisting of hydrogen, halogen, hydroxyl, azide, alkoxyl,        sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,        carboxyl, cyano, silyl, ether, alkylthio, sulfonyl, sulfonamido,        ketone, aldehyde, substituted or unsubstituted amine,        substituted or unsubstituted amide, nitro, ester, morpholino,        dioxolane, substituted or unsubstituted alkyl, substituted or        unsubstituted alkylhalide, substituted or unsubstituted aralkyl,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted cycloalkyl; substituted or        unsubstituted heterocyclyl; substituted or unsubstituted        cycloalkenyl, substituted or unsubstituted aryl, substituted or        unsubstituted heteroaryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted heteroalkyl, substituted        or unsubstituted alkylheteroaryl, and combinations thereof; and    -   each of the variables R³, R⁴, R⁵, R⁶, R⁷, R⁸, x, and the        bond - - - is as described above and described and defined in WO        2017/161119, the entirety of each of which is herein        incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-t:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R³, R⁴, R⁵, R⁶, R⁷, R′, x, and the bond - - - is asdescribed above for I-o and described and defined in WO 2017/161119, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-u:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R³, R⁴, R⁵, R⁸, L, and the bond - - - is as describedabove for I-o and described and defined in WO 2017/161119, the entiretyof each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-v:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R¹, R³, R⁴, R⁵, L, y, and the bond - - - is as describedabove for I-o and described and defined in WO 2017/161119, the entiretyof each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-x:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables A, B, C, W, X, Y, and Z is as described and defined inU.S. Pat. No. 5,721,246, the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

a DCAF15 E3 ubiquitin ligase binding moiety

or a VHL E3 ubiquitin ligase binding moiety

thereby forming a compound of formula I-y-1, I-y-2, or I-y-3:

or a pharmaceutically acceptable salt thereof, wherein IRAK is asdefined above and described in embodiments herein, and wherein:

-   -   each of X¹, X², and X³ is independently a bivalent moiety        selected from a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

-   -   each of X⁴ and X⁵ is independently a bivalent moiety selected        from —CH₂—, —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   each of R², R³, and R⁴ is independently hydrogen, —R⁶, halogen,        —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen or C₁₋₆ aliphatic;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring A is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-2 heteroatoms independently selected from nitrogen,        oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   Ring B is selected from 6-membered aryl containing 0-2 nitrogen        atoms or a 8-10 membered bicyclic heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   Ring C is a selected from 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   L is a covalent bond or a bivalent, saturated or unsaturated,        straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6        methylene units of L are independently replaced by -Cy-, —O—,        —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—,        —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein:

-   -   each -Cy- is independently an optionally substituted bivalent        ring selected from phenylenyl, an 8-10 membered bicyclic        arylenyl, a 4-7 membered saturated or partially unsaturated        carbocyclylenyl, a 4-7 membered saturated or partially        unsaturated spiro carbocyclylenyl, an 8-10 membered bicyclic        saturated or partially unsaturated carbocyclylenyl, a 4-7        membered saturated or partially unsaturated heterocyclylenyl        having 1-2 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, a 4-7 membered saturated or partially        unsaturated spiro heterocyclylenyl having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, an        8-10 membered bicyclic saturated or partially unsaturated        heterocyclylenyl having 1-2 heteroatoms independently selected        from nitrogen, oxygen, and sulfur, a 5-6 membered heteroarylenyl        having 1-4 heteroatoms independently selected from nitrogen,        oxygen, and sulfur, or an 8-10 membered bicyclic heteroarylenyl        having 1-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   m is 0, 1, 2, 3 or 4;    -   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;    -   p is 0, 1, 2, 3 or 4;    -   q is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-y′-1 or I-y″-1:

or a pharmaceutically acceptable salt thereof, wherein IRAK, L, Ring A,X¹, X², X³, R¹, R² and m are as described above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-z-1, I-z-2, or I-z-3respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and        IRAK are as defined above and described herein, and wherein:    -   W¹ is CR⁶R⁷, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   W² is CR⁸R⁹, C═O, C═S, C═CH₂, SO₂, S(O), P(O)Oalkyl,        P(O)NHalkyl, P(O)N(alkyl)₂, P(O)alkyl, P(O)OH, P(O)NH₂;    -   X is independently selected from NH, NR³, CH₂, CHR³, C(R³)₂, O,        and S;    -   n is 0, 1, 2, or 3;    -   is a single or double bond;    -   wherein when        represents a single bond, n is 0, 1, 2, or 3;    -   wherein when        represents a double bond, n is 0, 1, or 2;    -   R¹ is selected from:

and R¹*:

-   -   or R¹ is selected from:

-   -   R² is alkyl, hydrogen, aliphatic, heteroaliphatic, aryl,        heteroaryl or heterocyclic;    -   or R¹ and R² are combined to form a 4, 5, 6, 7, 8, 9, or 10        membered heterocyclo or heteroaryl species, wherein the        heterocyclo or heteroaryl species is substituted with R¹² at any        desired position, wherein the heterocyclo or heteroaryl species        is optionally further substituted with one or more substituents        selected from R⁵;    -   R¹* is selected from:

-   -   R³ is selected at each instance from: alkyl, —C(O)H, —C(O)OH,        —C(O)alkyl, —C(O)Oalkyl, alkene, and alkyne, aliphatic,        heteroaliphatic, aryl, heteroaryl and heteroalkyl;    -   R⁴ is selected at each instance from: alkyl, alkene, alkyne,        halogen, hydroxyl, alkoxy, azide, amino, cyano, —NH(aliphatic),        —N(aliphatic)₂, —NHSO₂(aliphatic), —N(aliphatic)SO₂alkyl,        —NHSO₂(aryl, heteroaryl or heterocyclic), —N(alkyl)SO₂(aryl,        heteroaryl or heterocyclic) —NHSO₂alkenyl, —N(alkyl)SO₂alkenyl,        —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, and haloalkyl; aliphatic,        heteroaliphatic, aryl, heteroaryl, heteroalkyl and carbocyclic;    -   or two R⁴ substituents together with the carbon atom(s) to which        they are bound can form a 3, 4, 5 or 6 membered ring; R⁵ and R¹⁴        are selected at each instance from: hydrogen, alkyl, alkene,        alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano,        —NH(aliphatic), —N(aliphatic)₂, —NHSO₂(aliphatic),        —N(aliphatic)SO₂alkyl, —NHSO₂(aryl, heteroaryl or heterocyclic),        —N(alkyl)SO₂(aryl, heteroaryl or heterocyclic) —NHSO₂alkenyl,        —N(alkyl)SO₂alkenyl, —NHSO₂alkynyl, —N(alkyl)SO₂alkynyl, and        haloalkyl; aliphatic, heteroaliphatic, aryl, heteroaryl,        heteroalkyl and carbocyclic;    -   or R⁵ is independently selected from C(O)R⁴, cyano, aryl,        aryloxy, heterocyclo, heteroaryl, arylalkyl, alkoxy, hydroxyl,        O-arylalkyl, or cycloalkyl;    -   R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹, are independently selected from        hydrogen, alkyl, aliphatic, heteroaliphatic, hydroxyl, alkoxy,        amine, —NH(aliphatic), and —N(aliphatic)₂;    -   or R⁶ and R⁷ together with the carbon to which they are bound        form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-,        or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms        selected from N and O;    -   or R⁸ and R⁹ together with the carbon to which they are bound        form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-,        or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms        selected from N and O;    -   or R¹⁰ and R¹¹ together with the carbon to which they are bound        form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-,        or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms        selected from N and O;    -   or R⁶ and R⁸ form a 1 or 2 carbon bridged ring;    -   or R⁶ and R¹⁰ form a 1 or 2 carbon bridged ring;    -   or R⁸ and R¹⁰ form a 1 or 2 carbon bridged ring;    -   or R¹⁴ and R⁶ form a 3, 4, 5, or 6 carbon fused ring;    -   or R¹⁴ and R¹⁰ form a 3, 4, 5, or 6 carbon fused ring;    -   or R¹⁴ and R⁸ form a 1 or 2 carbon bridged ring;    -   or R¹⁴ and R⁴ form a 3, 4, 5, or 6 carbon fused ring wherein R⁵        is on the carbon alpha to R¹⁴ or a 1, 2, 3, or 4 carbon bridged        ring wherein R⁵ is not on the carbon alpha to R¹⁴;    -   R¹² is L;    -   R^(1′) is selected from

-   -   Y is independently selected from N, CH, or CR¹⁰¹, wherein 0, 1,        2, or 3 instances of Y are selected to be N;    -   R¹⁰¹ is independently selected at each occurrence from hydrogen,        alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl,        heteroaryl, heterocycle, arylalkyl, heteroarylalkyl,        heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH,        NO₂, F, Cl, Br, I, CF₃, NH₂, NHalkyl, N(alkyl)₂, aliphatic, and        heteroaliphatic as defined in WO 2017/197051, the entirety of        which is herein incorporated by reference, and wherein

is attached to R¹, the ring formed by combining R¹ and R², or R¹⁷ at thesite of attachment of R¹² as defined in WO 2017/197051 such that

takes the place of the R¹² substituent.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-aa:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein Ring B is other than imidazo or benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

or wherein

-   -   Ring B is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-2 heteroatoms independently selected from nitrogen,        oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-aa′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring A is a bi- or tricyclic ring selected from

wherein Ring B is other than imidazo or benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

wherein Ring B is other than benzo,

or wherein

-   -   Ring B is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-3 heteroatoms independently selected from boron,        nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl        with 1-3 heteroatoms independently selected from nitrogen,        oxygen or sulfur;    -   R³ is selected from hydrogen, halogen, —OR, —N(R)₂, or —SR;    -   each R⁴ is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:    -   two R groups on the same nitrogen are optionally taken together        with their intervening atoms to form a 4-7 membered saturated,        partially unsaturated, or heteroaryl ring having 0-3        heteroatoms, in addition to the nitrogen, independently selected        from nitrogen, oxygen, and sulfur.

In some embodiments, the compound of formula I-aa′ above is provided asa compound of formula I-aa″ or formula I-aa′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, L, R¹, R², X¹, X², X³, and m is as defined        above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-bb:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring A and        Ring B is connected to

and

-   -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-bb′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1, wherein when p is 0, the bond connecting Ring A and        Ring B is connected to

and

-   -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-cc:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR,        —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ a aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, the compound of formula I-bb′ above is provided asa compound of formula I-bb″ or formula I-bb′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, Ring B, L, R¹, R², R³, X¹, X², X³, p, and        m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (cereblon) bindingmoiety

thereby forming a compound of formula I-cc′:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein:

-   -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   Ring A is a mono- or bicyclic ring selected from

-   -   each R² is independently hydrogen, deuterium, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —Si(R)₃, —S(O)₂R, —S(O)₂NR₂, —S(O)R,        —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂,        —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   Ring B is selected from a 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   each of R³ and R⁴ is independently hydrogen, —R⁶, halogen, —CN,        —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen, C₁₋₄ aliphatic, or —CN;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   m is 0, 1, or 2;    -   n is 0, 1, 2, 3, or 4;    -   p is 0 or 1; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, a compound of formula I-cc′ above is provided as acompound of formula I-cc″ or formula I-cc′″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, Ring B, L, R¹, R², R³, X¹, X², X³, p, n,        and m is as defined above.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK-4 inhibitor

thereby forming a compound of formula I-dd-1 or I-dd-2 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   A is optionally substituted heteroaryl, optionally substituted        aryl, optionally substituted heterocycloalkyl, optionally        substituted cycloalkyl, optionally substituted        (cycloalkyl)alkyl, optionally substituted        (heterocycloalkyl)alkyl, optionally substituted aralkyl,        optionally substituted heteroaralkyl, optionally substituted        cycloalkyl-NR_(x)—, optionally substituted        heterocycloalkyl-NR_(x)—, optionally substituted aryl-NR_(x)—,        optionally substituted heteroaryl-NR_(x)—, optionally        substituted cycloalkyl-O—, optionally substituted        heterocycloalkyl-O—, optionally substituted aryl-O— or        optionally substituted heteroaryl-O—; e.g., wherein each        optional substituent independently represents an occurrence of        R_(z);    -   B is hydrogen, halogen, cyano, optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkoxy,        —NR_(a)R_(b), optionally substituted cycloalkyl, optionally        substituted aryl, optionally substituted heterocycloalkyl,        optionally substituted heteroaryl, optionally substituted        (cycloalkyl)alkyl, optionally substituted        (heterocycloalkyl)alkyl, optionally substituted aralkyl,        optionally substituted heteroaralkyl, optionally substituted        cycloalkyl-NR_(x)—, optionally substituted        heterocycloalkyl-NR_(x)—, optionally substituted aryl-NR_(x)—,        optionally substituted heteroaryl-NR_(x)—, optionally        substituted cycloalkyl-O—, optionally substituted        heterocycloalkyl-O—, optionally substituted aryl-O—, optionally        substituted heteroaryl-O—; e.g., wherein each optional        substituent independently represents an occurrence of R_(y);    -   Q is absent or optionally substituted heterocycloalkyl,        optionally substituted heteroaryl, optionally substituted aryl,        optionally substituted cycloalkyl, optionally substituted        (heterocycloalkyl)alkyl, optionally substituted        (heteroaryl)alkyl, optionally substituted aralkyl, optionally        substituted (cycloalkyl)alkyl, —NR₃R₄, —O—R₃ or —S—R; e.g.,        wherein each optional substituent independently represents an        occurrence of R_(z);    -   W is N or CH;    -   R₁ is hydrogen, optionally substituted alkyl, optionally        substituted cycloalkyl, optionally substituted        (cycloalkyl)alkyl, optionally substituted        (heterocycloalkyl)alkyl, optionally substituted        heterocycloalkyl, optionally substituted aralkyl, optionally        substituted (heteroaryl)alkyl-, optionally substituted        alkoxyalkyl, optionally substituted aminoalkyl, or        —(CH₂)_(m)—R₂; e.g., wherein each optional substituent        independently represents halo, hydroxy, alkoxy, amino, nitro,        cycloalkyl, aryl, heterocycloalkyl or heteroaryl;    -   R₂ is hydrogen, —NR_(a)R_(b), alkoxy, hydroxy, optionally        substituted heteroaryl or optionally substituted        heterocycloalkyl; e.g., wherein each optional substituent        independently represents an occurrence of R_(y);    -   each R₃ and R₄ is independently selected from optionally        substituted aryl, optionally substituted cycloalkyl, optionally        substituted heteroaryl, optionally substituted heterocycloalkyl,        optionally substituted aralkyl, optionally substituted        (cycloalkyl)alkyl, optionally substituted (heteroaryl)alkyl and        optionally substituted (heterocycloalkyl)alkyl; e.g., wherein        each optional substituent is independently selected from alkyl,        halo, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl,        amino, nitro, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl,        heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl and        (heteroaryl)alkyl;    -   each R_(a) and R_(b) is independently selected from hydrogen,        alkyl, aminoalkyl, acyl and heterocyclyl; or R_(a) and R_(b) are        taken together with the nitrogen to which they are attached to        form an optionally substituted ring;    -   R_(x) is hydrogen, alkyl, hydroxy, hydroxyalkyl, acyl or        cycloalkyl;    -   each R_(y) and R_(x) is independently selected from hydroxy,        hydroxyalkyl, halo, alkyl, oxo, haloalkyl, alkoxy, alkenyloxy,        amino, nitro, cyano, —SH, —S(alkyl), glycinate, ester,        thioester, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,        (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, aralkyl, and        (heteroaryl)alkyl; optionally wherein the hydroxy, hydroxyalkyl,        alkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are        further substituted by one or more substituents selected from        alkyl, halo, alkenyl, amino, nitro, cycloalkyl and        (cycloalkyl)alkyl; or    -   R_(y) and R_(z) taken together with the atoms to which they are        attached form an alkyl chain having 1-10 carbon atoms;        optionally wherein 1-3 carbon atoms are replaced by O, NH or S;    -   m is 1, 2, or 3; and    -   n is 1 or 2;        as defined and described in WO 2017/009798 and US 2018/0201609,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ee-1, I-ee-2, I-ee-3, or I-ee-4respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is selected from phenyl and 5- or 6-membered heteroaryl;    -   Ring B is selected from phenyl and 5- or 6-membered heteroaryl;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2;    -   one of W and X is N, and the other of W and X is C;    -   Y is N or C—R²    -   R¹ is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₆cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo,        —CN, —C(R^(1a))═NR(OR^(1a)), —C(R^(1a))═N(R^(1a)), —C(O)R^(1a),        —C(O)₂R^(1a), —C(O)N(R^(1a))₂, —NO₂, —N(R^(1a))₂,        —N(R^(1a))C(O)R^(1a), —N(R^(1a))C(O)₂R^(1a),        —N(R^(1a))C(O)N(R^(1a))₂, —N(R^(1a))S(O)₂R^(1a), —OR^(1a),        —OC(O)R^(1a), —OC(O)N(R^(1a))₂, —SR^(1a), —S(O)R^(1a),        —S(O)₂R^(1a), —S(O)N(R^(1a))₂, and —S(O)₂N(R^(1a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, and 3-        to 6-membered saturated heterocyclyl are optionally substituted        with one or more R¹⁰; or two R¹ substituents, together with        their intervening atoms, form a C₅₋₇cycloalkyl or a saturated 5-        to 7-membered heterocyclic ring, wherein said C₅₋₇cycloalkyl or        a saturated 5- to 7-membered heterocyclic ring are optionally        substituted with one or more R⁵;    -   R^(1a) in each occurrence is independently selected from H,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered monocyclic        carbocyclyl, and 3- to 6-membered monocyclic heterocyclyl        wherein said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to        6-membered monocyclic carbocyclyl, and 3- to 6-membered        monocyclic heterocyclyl in each occurrence are optionally and        independently substituted with one or more R¹⁰;    -   R¹⁰ in each occurrence is independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered carbocyclyl, 3- to        6-membered heterocyclyl, halo, —CN, —C(R^(10a))═NR(OR^(10a)),        C(R^(10a))═N(R^(10a)), —C(O)R^(10a), —C(O)₂R^(10a),        —C(O)N(R^(10a))₂, —NO₂, —N(R^(10a))₂, —N(R^(10a))C(O)R^(10a),        —N(R^(10a))C(O)₂R^(10a), —N(R^(10a))C(O)N(R^(10a))₂,        —N(R^(10a))S(O)₂R^(10a), —OR^(10a), OC(O)R^(10a),        —OC(O)N(R^(10a))₂, —SR^(10a), —S(O)R^(10a), —S(O)₂R^(10a),        —S(O)N(R^(10a))₂, and —S(O)₂N(R^(10a))₂;    -   R^(10a) in each occurrence is independently selected from H and        C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally substituted with        one or more halo;    -   R¹⁵ in each occurrence is independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered carbocyclyl, 3- to        6-membered heterocyclyl, halo, —CN, —C(R^(15a))═NR(OR^(15a)),        C(R^(15a))═N(R^(15a)), —C(O)R^(15a), —C(O)₂R^(15a),        —C(O)N(R^(15a))₂, —NO₂, —N(R^(15a))₂, —N(R^(15a))C(O)R^(15a),        —N(R^(15a))C(O)₂R^(15a), —N(R^(15a))C(O)N(R^(15a))₂,        —N(R^(15a))S(O)₂R^(15a), —OR^(15a), —OC(O)R^(15a),        —OC(O)N(R^(15a))₂, —SR^(15a), —S(O)R^(15a), —S(O)₂R^(15a),        —S(O)N(R^(15a))₂, and S(O)₂N(R^(15a))₂;    -   R^(15a) in each occurrence is independently selected from H and        C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally substituted with        one or more halo;    -   R² is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-        to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halo,        —CN, —C(R^(2a))═NR(OR^(2a)), —C(R^(2a))═N(R²), —C(O)R^(2a),        —C(O)₂R^(2a), —C(O)N(R^(2a))₂, —NO₂, —N(R^(2a))₂,        —N(R^(2a))C(O)R^(2a), —N(R^(2a))C(O)₂R^(2a),        —N(R^(2a))C(O)N(R^(2a))₂, —N(R^(2a))S(O)₂R^(2a), —OR^(2a),        —OC(O)R^(2a), —OC(O)N(R^(2a))₂, —SR^(2a), —S(O)R^(2a),        —S(O)₂R^(2a), —S(O)N(R^(2a))₂, and —S(O)₂N(R^(2a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 7-membered        carbocyclyl, and 3-7 membered heterocyclyl are optionally        substituted with one or more R²⁰;    -   R^(2a) in each occurrence is independently selected from H and        C₁₋₆alkyl, wherein said C₁₋₆alkyl in each occurrence is        optionally and independently substituted with one or more R²⁰;    -   R²⁰ in each occurrence is independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, 3- to 7-membered        saturated heterocyclyl, halo, —CN, —C(R^(20a))═NR(OR^(20a)),        —C(R^(20a))═N(R^(20a)), C(O)R^(20a), —C(O)₂R^(20a),        —C(O)N(R^(20a))₂, —NO₂, —N(R^(20a))₂, —N(R^(20a))C(O)R^(20a),        N(R^(20a))C(O)₂R^(20a), —N(R^(20a))C(O)N(R^(20a))₂,        —N(R^(20a))S(O)₂R^(20a), —OR^(20a), —OC(O)R^(20a),        OC(O)N(R^(20a))₂, —SR^(20a), —S(O)R^(20a), —S(O)₂R^(20a),        —S(O)N(R^(20a))₂, and —S(O)₂N(R^(20a))₂, wherein said C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, and 3-7 membered        saturated heterocyclyl in each occurrence are optionally and        independently substituted with one or more R²⁵;    -   R^(20a) in each occurrence is independently selected from H and        C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally substituted with        R²⁵;    -   R²⁵ is selected from halo and —OR^(25a);    -   R^(25a) is selected from H and C₁₋₆alkyl;    -   R³ is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₆cycloalkyl, 3- to 6-membered saturated heterocyclyl, halo,        —CN, —C(R^(3a))═NR(OR^(3a)), —C(R^(3a))═N(R^(3a)), —C(O)R^(3a),        —C(O)₂R^(3a), C(O)N(R^(3a))₂, —NO₂, —N(R^(3a))₂,        —N(R^(3a))C(O)R^(3a), —N(R^(3a))C(O)₂R^(3a),        —N(R^(3a))C(O)N(R^(3a))₂, —N(R^(3a))S(O)₂R^(3a), —OR^(3a),        —OC(O)R^(3a), —OC(O)N(R^(3a))₂, —SR^(3a), —S(O)R^(3a),        —S(O)₂R^(3a), —S(O)N(R^(3a))₂, and —S(O)₂N(R^(3a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, and 3-        to 6-membered saturated heterocyclyl are optionally substituted        with one or more R³⁰;    -   R^(3a) in each occurrence is independently selected from H,        C₁₋₆alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered        heterocyclyl, wherein said C₁₋₆alkyl, 3- to 6-membered        carbocyclyl, and 3- to 6-membered heterocyclyl in each        occurrence are optionally and independently substituted with one        or more R³⁰;    -   R³⁰ in each occurrence is independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered carbocyclyl, 3- to        6-membered heterocyclyl, halo, —CN, —C(R^(30a))═NR(OR^(30a)),        C(R^(30a))═N(R^(30a)), —C(O)R^(30a), —C(O)₂R^(30a),        —C(O)N(R^(30a))₂, —NO₂, —N(R^(30a))₂, —N(R^(30a))C(O)R^(30a),        —N(R^(30a))C(O)₂R^(30a), —N(R^(30a))C(O)N(R^(30a))₂,        —N(R^(30a))S(O)₂R^(30a), —OR^(30a), OC(O)R^(30a),        —OC(O)N(R^(30a))₂, —SR^(30a), —S(O)R^(30a) S(O)₂R^(30a),        —S(O)N(R^(30a))₂, and —S(O)₂N(R^(30a))₂, wherein said C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, 3-6 membered carboyclyl, 3- to        6-membered heterocyclyl in each occurrence are optionally and        independently substituted with one or more R³⁵;    -   R^(30a) in each occurrence is independently selected from H and        C₁₋₄alkyl, wherein C₁₋₄alkyl is optionally substituted with one        or more R³⁵;    -   R³⁵ in each occurrence is independently selected from halo and        —OR^(35a);    -   R^(35a) in each occurrence is independently selected from H and        C₁₋₆alkyl;    -   R⁴ is selected from H, halo, C₁₋₆alkyl, N(R^(4a))₂, and        —OR^(4a); and    -   R^(4a) in each occurrence is independently selected from H and        C₁₋₆alkyl;        as defined and described in WO 2016/011390 and US 2017/0204093,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ff-1, I-ff-2, I-ff-3, or I-ff-4respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is selected from phenyl and 5- or 6-membered heteroaryl;    -   Ring B is selected from phenyl and 5- or 6-membered heteroaryl;    -   Ring C is a 3- to 6-membered carbocyclyl,    -   n is 1, 2 or 3;    -   p is 0, 1, or 2;    -   one of W and X is N, and the other of W and X is C;    -   Y is N or CR    -   R¹ is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, halo,        —CN, —C(R^(1a))═NR(OR^(1a)), —C(R^(1a))═N(R^(1a)), —C(O)R^(1a),        —C(O)₂R^(1a), —C(O)N(R^(1a))₂, —NO₂, —N(R^(1a))₂,        —N(R^(1a))C(O)R^(1a), —N(R^(1a))C(O)₂R^(1a),        —N(R^(1a))C(O)N(R^(1a))₂, —N(R^(1a))S(O)₂R^(1a), —OR^(1a),        —OC(O)R^(1a), —OC(O)N(R^(1a))₂, —SR^(1a), —S(O)R^(1a),        —S(O)₂R^(1a), —S(O)N(R^(1a))₂, and —S(O)₂N(R^(1a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, and C₂₋₆alkynyl are optionally        substituted with one or more    -   R^(1a) in each occurrence is independently selected from H or        C₁₋₆alkyl wherein said C₁₋₆alkyl in each occurrence are        optionally and independently substituted with one or more    -   R¹⁰ in each occurrence is independently selected from halo, —CN,        —C(R^(10a))═NR(OR)^(10a), —C(R^(10a))═N(R^(10a)), —C(O)R^(10a),        —C(O)₂R^(10a), —C(O)N(R^(10a))₂, —NO₂, —N(R^(10a))₂,        —N(R^(10a))C(O)R^(10a), —N(R^(10a))C(O)₂R^(10a),        —N(R^(10a))C(O)N(R^(10a))₂, —N(R^(10a))S(O)₂R^(10a), —OR^(10a),        —OC(O)R^(10a), —OC(O)N(R^(10a))₂, —SR^(10a), —S(O)R^(10a),        —S(O)₂R^(10a), —S(O)N(R^(10a))₂, and —S(O)₂N(R^(10a))₂;    -   R^(10a) in each occurrence is independently selected from H and        C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally substituted with        one or more halo;    -   R is selected from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to        7-membered carbocyclyl, 3-to 7-membered heterocyclyl, halo, —CN,        —C(R^(2a))═NR(OR^(2a)), —C(R^(2a))═N(R^(2a)), —C(O)R^(2a),        —C(O)₂R^(2a), —C(O)N(R^(2a))₂, —NO₂, —N(R^(2a))₂,        —N(R^(2a))C(O)R^(2a), —N(R^(2a))C(O)₂R^(2a),        —N(R^(2a))C(O)N(R^(2a))₂, —N(R^(2a))S(O)₂R^(2a), —OR^(2a),        —OC(O)R^(2a), —OC(O)N(R^(2a))₂, —SR^(2a), —S(O)R^(2a),        —S(O)₂R^(2a), —S(O)N(R^(2a))₂, and —S(O)₂N(R^(2a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, 3-to 7-membered        carbocyclyl, and 3-7 membered heterocyclyl are optionally        substituted with one or more R²⁰;    -   R^(2a) in each occurrence is independently selected from H and        C₁₋₆alkyl, wherein said C₁₋₆alkyl in each occurrence is        optionally and independently substituted with one or more R²⁰;    -   R²⁰ in each occurrence is independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, 3-to 7-membered        saturated heterocyclyl, halo, —CN, —C(R^(20a))═NR(OR^(20a)),        —C(R^(20a))═N(R^(20a)), —C(O)R^(20a), —C(O)₂R^(20a),        —C(O)N(R^(20a))₂, —NO₂, —N(R^(20a))₂, —N(R^(20a))C(O)R^(20a),        —N(R^(20a))C(O)₂R^(20a), —N(R^(20a))C(O)N(R^(20a))₂,        —N(R^(20a))S(O)₂R^(20a), —OR^(20a), —OC(O)R^(20a),        —OC(O)N(R^(20a))₂, —SR^(20a), —S(O)R^(20a), —S(O)₂R^(20a),        —S(O)N(R^(20a))₂, and —S(O)₂N(R^(20a))₂, wherein said C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₇cycloalkyl, and 3-7 membered        saturated heterocyclyl in each occurrence are optionally and        independently substituted with one or more R²⁵;    -   R^(20a) in each occurrence is independently selected from H and        C₁₋₆alkyl, wherein said C₁₋₆alkyl is optionally substituted with        R²⁵;    -   R²⁵ is selected from halo and —OR^(25a);    -   R^(25a) is selected from H and C₁₋₆alkyl;    -   R is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₆cycloalkyl, 3-to 6-membered saturated heterocyclyl, halo,        —CN, —C(R^(3a))═NR(OR^(3a)), —C(R^(3a))═N(R^(3a)), —C(O)R^(3a),        —C(O)₂R^(3a), —C(O)N(R^(3a))₂, —NO₂, —N(R^(3a))₂,        —N(R^(3a))C(O)R^(3a), —N(R^(3a))C(O)₂R^(3a),        —N(R^(3a))C(O)N(R^(3a))₂, —N(R^(3a))S(O)₂R^(3a), —OR^(3a),        —OC(O)R^(3a), —OC(O)N(R^(3a))₂, —SR^(3a), —S(O)R^(3a),        —S(O)₂R^(3a), —S(O)N(R^(3a))₂, and —S(O)₂N(R^(3a))₂, wherein        said C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, and        3-to 6-membered saturated heterocyclyl are optionally        substituted with one or more R³⁰;    -   R^(3a) in each occurrence is independently selected from H,        C₁₋₆alkyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered        heterocyclyl, wherein said C₁₋₆alkyl, 3- to 6-membered        carbocyclyl, and 3- to 6-membered heterocyclyl in each        occurrence are optionally and independently substituted with one        or more R³⁰;    -   R³⁰ in each occurrence is independently selected from C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, 3- to 6-membered carbocyclyl, 3-to        6-membered heterocyclyl, halo, —CN, —C(R^(30a))═NR(OR^(30a)),        —C(R^(30a))═N(R^(30a)), —C(O)R^(30a), —C(O)₂R^(30a),        —C(O)N(R^(30a))₂, —NO₂, —N(R^(30a))₂, —N(R^(30a))C(O)R^(30a),        —N(R^(30a))C(O)₂R^(30a), —N(R^(30a))C(O)N(R^(30a))₂,        —N(R^(30a))S(O)₂R^(30a), —OR^(30a), —OC(O)R^(30a),        —OC(O)N(R^(30a))₂, —SR^(30a), —S(O)R^(30a), —S(O)₂R^(30a),        —S(O)N(R^(30a))₂, and —S(O)₂N(R^(30a))₂, wherein said C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, 3-6 membered carbocyclyl, 3- to        6-membered heterocyclyl in each occurrence are optionally and        independently substituted with one or more R³⁵;    -   R^(30a) in each occurrence is independently selected from H and        C₁₋₄alkyl, wherein C₁₋₄alkyl is optionally substituted with one        or more R³⁵;    -   R³⁵ in each occurrence is independently selected from halo and        —OR^(35a); and    -   R^(35a) in each occurrence is independently selected from H and        C₁₋₆alkyl;        as defined and described in WO 2017/127430, the entirety of        which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-gg-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   HET is a heteroaryl selected from pyrrolo[2,3-b]pyridinyl,        pyrrolo[2,3-d]pyrimidinyl, pyrazolo[3,4-b]pyridinyl,        pyrazolo[3,4-d]pyrimidinyl, imidazolo[4,5-b]pyridinyl, and        imidazolo[4,5-d]pyrimidinyl, wherein said heteroaryl is attached        to the pyridinyl group in the compound of Formula (I) by a        nitrogen ring atom in said heteroaryl and wherein said        heteroaryl is substituted with zero to 2 R_(b);    -   A is pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxadiazolyl        or dihydroisoxazolyl, each substituted with R_(a);    -   R₃ is C₂₋₃ alkyl, C₂₋₃ fluoroalkyl, C₃₋₄ hydroxyalkyl, or a        cyclic group selected from C₃₋₆ cycloalkyl, oxetanyl,        tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, wherein        said cyclic group is substituted with zero to 2 substituents        independently selected from F, —OH, C₁₋₂ alkyl, and —CH₂CHF₂;    -   R^(a) is:    -   (i) H, F, Cl, —OH, —CN, C₁₋₆ alkyl, C₁₋₆ fluoroalkyl, C₁₋₄        cyanoalkyl, C₁₋₆ hydroxyalkyl, C₁₋₅ hydroxy-fluoroalkyl, C₂₋₄        alkenyl, C₁₋₆aminoalkyl, —(CH₂)₁₋₃NHR_(y), —(CH₂)₁₋₃NR_(y)R_(y),        —CH₂CH(OH)(phenyl), —CH(CH₂OH)(phenyl), —CH₂CH(OH)CH₂(phenyl),        —CH₂CH(OH)CH₂O(methoxyphenyl), —CH₂CH(NH₂)CH₂(phenyl),        —(CH₂CH₂O)₄H, —(CH₂)₁₋₃O(C₁₋₃ alkyl), —CH₂CH(OH)CH₂O(C₁₋₃alkyl),        —CH₂C(O)(C₁₋₃ alkyl), —CH₂C(O)NR_(y)R_(y),        —(CH₂)₁₋₃NR_(y)C(O)(C₁₋₃ alkyl), —CH₂C(O)O(C₁₋₃ alkyl),        —C(O)NH₂, —CH₂NR_(y)C(O)NH₂, —(CH₂)₁₋₂NR_(y)C(O)O(C₁₋₂ alkyl),        —(CR_(y)R_(y))₁₋₅OC(O)CH₂NR_(y)R_(y), —CH₂CH₂S(O)₂CH₃,        —CH₂S(O)₂(C₁₋₃ alkyl), —CH₂S(O)₂(phenyl), or        —NH(aminocyclohexyl); or    -   (ii) —(CH₂)₀₋₃R_(z) or —(CH₂)₀₋₁C(O)R_(z), wherein R_(z) is C₃₋₆        cycloalkyl, azetidinyl, oxetanyl, tetrahydrofuranyl,        tetrahydropyranyl, piperidinyl, piperazinyl, pyrrolyl,        pyrrolidinonyl, morpholinyl, pyrrolidinyl, phenyl, pyrazolyl,        imidazolyl, pyridinyl, pyrimidinyl, dioxopyrimidinyl,        benzo[d]imidazolyl, benzo[d]thiazolyl, 1,3-dioxolanyl, or        8-azabicyclo[3.2.1]octanyl, each substituted with zero to 4        substituents independently from F, —CN, —OH, —NR_(y)R_(y), C₁₋₃        alkyl, C₁₋₃ fluoroalkyl, C₁₋₃ hydroxyalkyl, —CH(phenyl)₂,        —O(C₁₋₄ alkyl), —C(O)(C₁₋₄ alkyl), —C(O)(C₁₋₄ deuteroalkyl),        —C(O)(C₁₋₅ hydroxyalkyl), —C(O)(C₁₋₃ fluoroalkyl), —C(O)(C₃₋₆        cycloalkyl), —C(O)O(C₁₋₃ alkyl), —C(O)NR_(y)R_(y),        —C(O)(phenyl), —C(O)(pyridinyl), —C(O)CH₂(C₃₋₆ cycloalkyl),        —C(O)O(C₁₋₄ alkyl), —NH(C₁₋₄ alkyl), —NH(C₁₋₃ fluoroalkyl),        —NHC(O)CH₃, —NHC(O)O(C₁₋₃ alkyl), —NHC(O)OC(CH₃)₃, —S(O)₂(C₁₋₃        alkyl), —OS(O)₂(C₁₋₃ alkyl), methyl oxadiazolyl, and        pyrimidinyl;    -   each R_(b) is independently selected from H, Cl, —CN, —NH₂, and        —C(O)NH₂, wherein said heteroaryl is attached to the pyridinyl        group by a nitrogen atom in said heteroaryl; and    -   each R_(y) is independently H or C₁₋₂ alkyl;        as defined and described in WO 2016/210034 and US 2018/0186799,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-hh-1, I-hh-2, I-hh-3, or I-hh-4respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   each X₁, X₂ and X₃ are independently CR² or N;    -   A is O, S, S(O) or S(O)₂;    -   Z₁ is optionally substituted heteroaryl, optionally substituted        heterocycloalkyl, optionally substituted aryl, optionally        substituted cycloalkyl, optionally substituted        (heterocycloalkyl)alkyl-, optionally substituted aralkyl-,        optionally substituted heteroaralkyl-, optionally substituted        (cycloalkyl)alkyl-, optionally substituted aryloxy-, optionally        substituted heteroaryloxy-, optionally substituted        heterocycloalkyloxy-, optionally substituted cycloalkyloxy-,        optionally substituted aryl-NR′—, optionally substituted        heteroaryl-NR′—, optionally substituted heterocycloalkyl-NR′—,        optionally substituted cycloalkyl-NR′—, optionally substituted        aryl-S—, optionally substituted heteroaryl-S—, optionally        substituted heterocycloalkyl-S—, optionally substituted        cycloalkyl-S—, optionally substituted (cycloalkyl)alkyl-NR′—,        optionally substituted aralkyl-NR′—, optionally substituted        (heterocycloalkyl)alkyl-NR′—, optionally substituted        heteroaralkyl-NR′—, optionally substituted (cycloalkyl)alkyl-S—,        optionally substituted aralkyl-S—, optionally substituted        (heterocycloalkyl)alkyl-S—, optionally substituted        heteroaralkyl-S—, optionally substituted (cycloalkyl)alkyl-O—,        optionally substituted aralkyl-O—, optionally substituted        (heterocycloalkyl)alkyl-O—, optionally substituted        heteroaralkyl-O—; e.g., wherein each optional substituent        independently represents an occurance of R_(x);    -   Z₂ is absent or optionally substituted cycloalkyl, optionally        substituted aryl, optionally substituted heterocycloalkyl,        optionally substituted heteroaryl, optionally substituted        aryloxy-, optionally substituted heteroaryloxy-, optionally        substituted cycloalkyloxy-, optionally substituted        heterocycloalkyloxy-, optionally substituted (cycloalkyl)alkyl-,        optionally substituted aralkyl-, optionally substituted        (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-,        optionally substituted (cycloalkyl)alkyl-NR″—, optionally        substituted aralkyl-NR″—, optionally substituted        (heterocycloalkyl)alkyl-NR″—, optionally substituted        heteroaralkyl-NR″—, optionally substituted (cycloalkyl)alkyl-O—,        optionally substituted aralkyl-O—, optionally substituted        (heterocycloalkyl)alkyl-O—, optionally substituted        heteroaralkyl-O—, optionally substituted (cycloalkyl)alkyl-S—,        optionally substituted aralkyl-S—, optionally substituted        (heterocycloalkyl)alkyl-S— or optionally substituted        heteroaralkyl-S—; e.g., wherein each optional substituent        independently represents an occurrence of R_(y);    -   Z₃ is optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heterocycloalkyl, optionally        substituted heteroaryl, optionally substituted aryloxy-,        optionally substituted heteroaryloxy-, optionally substituted        cycloalkyloxy-, optionally substituted heterocycloalkyloxy-,        optionally substituted (cycloalkyl)alkyl-, optionally        substituted aralkyl-, optionally substituted        (heterocycloalkyl)alkyl-, optionally substituted heteroaralkyl-,        optionally substituted (cycloalkyl)-NR′″—, optionally        substituted aryl-NR′″—, optionally substituted heteroaryl-NR′″—,        optionally substituted heterocycloalkyl-NR′″—, optionally        substituted aryl-S—, optionally substituted heteroaryl-S—,        optionally substituted cycloalkyl-S—, optionally substituted        heterocycloalkyl-S—, optionally substituted        (cycloalkyl)alkyl-NR′″—, optionally substituted aralkyl-NR′″—,        optionally substituted (heterocycloalkyl)alkyl-NR′″—, optionally        substituted heteroaralkyl-NR′″—, optionally substituted        (cycloalkyl)alkyl-O—, optionally substituted aralkyl-O—,        optionally substituted (heterocycloalkyl)alkyl-O—, optionally        substituted heteroaralkyl-O—, optionally substituted        (cycloalkyl)alkyl-S—, optionally substituted aralkyl-S—,        optionally substituted (heterocycloalkyl)alkyl-S— or optionally        substituted heteroaralkyl-S—; e.g., wherein each optional        substituent independently represents an occurance of R_(z);    -   each R² is independently selected from hydrogen, alkyl,        haloalkyl, halo, cyano, optionally substituted alkoxy,        optionally substituted cycloalkyl, optionally substituted        (cycloalkyl)alkyl-, optionally substituted cycloalkyloxy-,        optionally substituted aryl, optionally substituted aralkyl-,        optionally substituted heterocycloalkyl, optionally substituted        heteroaryl, optionally substituted (heterocycloalkyl)alkyl-,        optionally substituted heteroaralkyl-, —NR_(a)R_(b), —O—R₃ and        —S—R₃; e.g., wherein each optional substituent independently        represents alkyl, alkoxy, halo, haloalkyl, hydroxy,        hydroxyalkyl, —SH, —S(alkyl), cyano, amido, amino, carboxylate,        glycinate, alaninate, oxo, aryl, cycloalkyl, heterocycloalkyl or        heteroaryl;    -   each R′, R″ and R′″ is independently selected from hydrogen,        alkyl, hydroxy, hydroxyalkyl, acyl and cycloalkyl;    -   each R_(x), R_(y) and R_(z) is independently selected from        alkyl, alkenyl, alkynyl, halo, hydroxy, haloalkyl, hydroxyalkyl,        aminoalkyl, alkoxy, —SH, —S(alkyl), cyano, amido, carboxylic        acid, carboxylate, ester, thioester, alkoxycarbonyl,        —C(O)NH(alkyl), oxo, cycloalkyl, cycloalkyloxy,        (cycloalkyl)alkyl-, aryl, aralkyl-, heterocycloalkyl,        heteroaryl, (heterocycloalkyl)alkyl-, heteroaralkyl-,        —NR_(a)R_(b), —O—R₄ or —S—R₄; optionally wherein the cycloalkyl,        aryl, heterocycloalkyl, and heteroaryl are further substituted        by one or more substituents selected from halo, haloalkyl,        amino, hydroxy, alkyl, cyano, nitro, alkenyl, aminoalkyl,        hydroxyalkyl and haloalkoxy;    -   each R_(a) and R_(b) is independently selected from hydrogen,        alkyl, aminoalkyl, acyl, aminoacyl, halo, haloalkyl, hydroxy,        haloalkoxy, hydroxyalkyl, nitro, cyano, cycloalkyl,        heterocycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl-,        (heterocycloalkyl)alkyl-, aralkyl-, and (heteroaryl)alkyl-;        optionally wherein the cycloalkyl, heterocycloalkyl, aryl and        heteroaryl are further substituted by one or more substituents        selected from alkyl, halo, alkenyl, cyano, hydroxy,        hydroxyalkyl, alkoxy, amino and nitro; or    -   R_(a) and R_(b) are taken together along with the atoms which        they are attached to form a 3 to 8 membered optionally        substituted ring; and    -   each R₃ and R₄ is independently selected from hydrogen, alkyl,        aminoacyl, phosphate, phosphonate, alkylphosphate,        alkoxycarbonyl, cycloalkyl, (cycloalkyl)alkyl-, aryl,        heteroaryl, heterocycloalkyl, aralkyl-, heteroaralkyl and        (heterocycloalkyl)alkyl-;        as defined and described in WO 2017/009806 and US 2018/0208605,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ii-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is CR or N;    -   A is O, S, SO₂, SO, —NRC(O), —NRSO₂, or N(R); or A is absent;    -   R³ is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,        —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or        —N(R)₂; or    -   when A is —NRC(O), —NRSO₂, or N(R); then R and R³, together with        the atoms to which each is attached, may form a 3-7 membered        heterocylic ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur; each of which is optionally        substituted;    -   X′ is CR or N;    -   Ring Z is a 3-7 membered heterocylic ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or a        5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; each of        which is optionally substituted;    -   R¹ is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,        —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or        —N(R)₂;    -   R^(a) is absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂,        —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂,        —NRSO₂R, or —N(R)₂;    -   Ring Y is an optionally substituted 5-6 membered monocyclic        heteroaryl ring having 2-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur;    -   R² is —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂, —SO₂R, —SOR,        —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂, —NRSO₂R, or        —N(R)₂;    -   R^(b) is absent, —R, halogen, -haloalkyl, —OR, —SR, —CN, —NO₂,        —SO₂R, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)N(R)₂,        —NRSO₂R, or —N(R)₂;    -   each R is independently hydrogen, C₁₋₆ aliphatic, C₃₋₁₀aryl, a        3-8 membered saturated or partially unsaturated carbocyclic        ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or a        5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; each of        which is optionally substituted; or        -   two R groups on the same atom are taken together with the            atom to which they are attached to form a C₃₋₁₀ aryl, a 3-8            membered saturated or partially unsaturated carbocyclic            ring, a 3-7 membered heterocylic ring having 1-4 heteroatoms            independently selected from nitrogen, oxygen, or sulfur, or            a 5-6 membered monocyclic heteroaryl ring having 1-4            heteroatoms independently selected from nitrogen, oxygen, or            sulfur; each of which is optionally substituted;            as defined and described in WO 2016/081679 and US            2016/0145252, the entirety of each of which is herein            incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-jj-1 or I-jj-2 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is NH or O;    -   b is 0 or 1;    -   n is 0, 1, 2, 3 or 4;    -   R₁ and R₂ are independently H, (C₁-C₄)alkyl and heterocyclyl, or        R₁ and R₂ can be taken together with the nitrogen to which they        are attached to form a monocyclic or bicyclic (fused, bridged or        spirocyclic) heterocycle containing 3-8 carbon atoms optionally        containing, in addition to the nitrogen, one or two additional        heteroatoms selected from N, O and S, said alkyl and heterocycle        are optionally substituted with one or more substituents        selected from R_(a);    -   R₃ is (C₁-C₄)alkyl wherein two adjacent alkyl groups can join        together and form a bridged moiety of 3-6 carbon atoms;    -   R₄ is absent, halo or O_(b)(C₁-C₄)alkyl;    -   R₅ is selected from C₁-C₄ alkyl and C₂-C₄ alkenyl which are        optionally substituted with one or more substituents selected        from R_(b);    -   R₆ is absent, halo, or O(C₁-C₄)alkyl;    -   R_(a) is halo, oxo, OH, O_(b)(C₁-C₄)alkyl, CF₃, SO₂(C₁-C₄)alkyl,        or heterocyclyl, said heterocyclyl optionally substituted with        one or more substituents independently selected from F, and        (C₁-C₄)alkyl; and    -   R_(b) is independently selected from OH, halo,        O_(b)(C₁-C₄)alkyl, and CN;        as defined and described in WO 2016/053769 and US 2017/0247388,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-kk-1 or I-kk-2 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   B is CH, N or S; D is CH or N; E is CH or N; F is CH or N; G is        CH or N; and J is C or N, wherein when    -   B is S then D is CH, E is N, F is CH, G is N and J is C;    -   X is O, S, CH₂ or N;    -   m is 0 or 1; n is 0, 1 or 2;    -   Ring A is pyridinyl, pyrazolyl, thiophenyl, furanyl or phenyl;    -   R₁ is independently selected from (C₁-C₄)alkyl, pyrimidine,        piperidine and phenyl, each optionally substituted with        (C₁-C₄)alkyl, OH, halo, O(C₁-C₄)alkyl, methylpiperidine,        S(O)₂R_(c), C(O)N(R_(b))₂, or C(O)O(C₁-C₄)alkyl;    -   R₂ is absent or H and R₃ is independently selected from:        (C₁-C₄)alkyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl,        thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl        each optionally substituted with one or more substituents        independently selected from halo, OH, oxo, N(R_(b))₂,        oxopyrrolidinyl, or morpholinyl, or R₂ and R₃ can be taken        together with the nitrogen to which they are attached to form        piperazine or morpholine, each optionally substituted with oxo;    -   R₄ is independently H or methyl;    -   R_(b) is independently selected from H and (C₁-C₄)alkyl; and    -   R_(c) is methyl;        as defined and described in WO 2016/144844 and US 2018/0051027,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-kk′-1 or I-kk′-2 respectively:

or a pharmaceutically acceptable salt thereof, wherein L and LBM are asdefined above and described in embodiments herein, and wherein each ofthe variables A, B, D, E, F, G, J, X, R₁, R₂, R₃ and n is as defined anddescribed in WO 2016/144844 and US 2018/0051027, the entirety of each ofwhich is herein incorporated by reference. Such IRAK4 inhibitors arewell known to one of ordinary skill in the art and include thosedescribed in Smith et al., Bioorg. Med. Chem., 2017, 27(12): 2721-2726and Lim et al., ACS Med. Chem. Lett., 2015, 6(6): 683-688.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ll-1 or I-ll′-2 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is aryl or heterocyclyl;    -   n is 0, 1, 2, 3 or 4;    -   R₁ is independently selected from: (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN, halo, said        alkyl, cycloalkyl and heterocyclyl optionally substituted with        halo, OH, CH₃, and OCH₃;    -   R₂ is H and R₃ is independently selected from: (C₁-C₆)alkyl,        (C₃-C₈)cycloalkyl, and heterocyclyl each optionally substituted        with one or more halo, OH, N(R_(b))₂, or morpholinyl, or R₂ and        R₃ can be taken together with the nitrogen to which they are        attached to form a heterocyclyl, said heterocyclyl optionally        substituted with one or more substituents selected from R_(a);    -   R_(a) is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, CF₃, CHF₂, OH, halo and NH₂, said alkyl        optionally substituted with (C₃-C₆)cycloalkyl and CF₃; and    -   R_(b) is independently selected from H and (C₁-C₄)alkyl;        as defined and described in WO 2016/144847 and US 2018/0051029,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-mm-1 or I-mm′-2 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is aryl or heterocyclyl;    -   n is 0, 1, 2, 3 or 4;    -   R₁ is independently selected from: (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN and halo, said        alkyl, cycloalkyl and heterocyclyl optionally substituted with        halo, OH, CH₃, and OCH₃;    -   R₂ is H and R₃ is independently selected from: (C₁-C₆)alkyl,        (C₃-C₈)cycloalkyl, and heterocyclyl each optionally substituted        with one or more halo, OH, N(R_(b))₂, or morpholinyl, or R₂ and        R₃ can be taken together with the nitrogen to which they are        attached to form a heterocyclyl, said heterocyclyl optionally        substituted with one or more substituents selected from R_(a);    -   R_(a) is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, CF₃, CHF₂, OH, halo and NH₂, said alkyl        optionally substituted with (C₃-C₆)cycloalkyl or CF₃; and    -   R_(b) is independently selected from H and (C₁-C₄)alkyl;        as defined and described in WO 2016/144846 and US 2018/0051028,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-nn-1 or I-nn′-2 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is aryl or heterocyclyl;    -   n is 0, 1, 2, 3 or 4;    -   R₁ is independently selected from: (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN, halo, said        alkyl, cycloalkyl and heterocyclyl optionally substituted with        halo, OH, CH₃, and OCH₃;    -   R₂ is H and R₃ is independently selected from: (C₁-C₆)alkyl,        (C₃-C₈)cycloalkyl, and heterocyclyl each optionally substituted        with one or more halo, OH, N(R_(b))₂, or morpholinyl, or R₂ and        R₃ can be taken together with the nitrogen to which they are        attached to form a heterocyclyl, said heterocyclyl optionally        substituted with one or more substituents selected from R_(a);    -   R_(a) is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, CF₃, CHF₂, OH, halo and NH₂, said alkyl        optionally substituted with (C₃-C₆)cycloalkyl and CF₃; and    -   R_(b) is independently selected from H and (C₁-C₄)alkyl;        as defined and described in WO 2016/144848 and US 2018/0051030,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-oo-1 or I-oo′-2 respectively:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is aryl or heterocyclyl;    -   n is 0, 1, 2, 3 or 4;    -   R₁ is independently selected from: (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, heterocyclyl, CF₃, CHF₂, CN, halo, said        alkyl, cycloalkyl and heterocyclyl optionally substituted with        halo, OH, CH₃, and OCH₃;    -   R₂ is H and R₃ is independently selected from: (C₁-C₆)alkyl,        (C₃-C₅)cycloalkyl and heterocyclyl each optionally substituted        with one or more halo, OH, N(R_(b))₂, or morpholinyl, or R₂ and        R₃ can be taken together with the nitrogen to which they are        attached to form a heterocyclyl, said heterocyclyl optionally        substituted with one or more substituents selected from R_(a);    -   R_(a) is independently selected from (C₁-C₄)alkyl,        (C₃-C₆)cycloalkyl, CF₃, CHF₂, OH, halo and NH₂, said alkyl        optionally substituted with (C₃-C₆)cycloalkyl and CF₃; and    -   R_(b) is independently selected from H and (C₁-C₄)alkyl;        as defined and described in WO 2016/144849 and US 2018/0051035,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and IRAK4 inhibitor

thereby forming a compound of formula I-pp-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-7 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   Ring B is

-   -   wherein        represents the portion of the ring fused to the pyrimidine ring        and # is -L²(R⁴)P—R^(X); each R¹ and R^(1′) is independently        —R², halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂,        —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,        —N(R)C(O)N(R)₂, Cy, or —N(R)S(O)₂R; or R¹ is selected from one        of the following formulae:

or

-   -   two R¹ groups are taken together with their intervening atoms to        form an optionally substituted 4-7 membered fused, spiro-fused,        or bridged bicyclic ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each Cy is independently an optionally substituted ring selected        from a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-10 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur; each R        is independently hydrogen, or an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, or sulfur;    -   each R² is independently an optionally substituted group        selected from C₁₋₆aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,        —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,        —N(R)C(O)R,    -   —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)₂N(R)₂,        —N(R)S(O)₂R, or an optionally substituted group selected from        C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or partially        unsaturated heterocyclic having 1-2 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-6 membered        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur;    -   R^(x) is hydrogen, —R², —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR,        —C(O)R, —N(R)₂, —NH[Ar], —OR, or —S(O)₂N(R)₂;    -   R^(z) is hydrogen, —R², —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR,        —C(O)R, —N(R)₂, —NH[Ar], —OR, or —S(O)₂N(R)₂;    -   [Ar] is phenyl or a 5-6 membered heteroaromatic ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, wherein [Ar] is substituted by m instances of R¹;    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   L² is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   m is 0-4;    -   n is 0-4; and    -   p is 0-2;        as defined and described in WO 2017/004133, the entirety of each        of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and IRAK4 inhibitor

thereby forming a compound of formula I-qq-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Y is N or C—R^(x);    -   Ring A is a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-7 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each R¹ and R^(v) is independently —R², halogen, —CN, —NO₂, —OR,        —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)C(O)N(R)₂, Cy, or        —N(R)S(O)₂R; or R¹ is selected from one of the following        formulas:

-   -   two R¹ groups are taken together with their intervening atoms to        form an optionally substituted 4-7 membered fused, spiro-fused,        or bridged bicyclic ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each Cy is independently an optionally substituted ring selected        from a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-10 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or: two        R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, or sulfur;    -   each R² is independently an optionally substituted group        selected from C₁₋₆aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each of R^(x) and R^(y) is independently hydrogen, —R², —CN,        —NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R, —N(R)₂, —H[Ar], —OR,        or —S(O)₂N(R)₂; or    -   R^(x) and R^(y) are taken together together with their        intervening atoms to form a 4-7 membered partially unsaturated        carbocyclic ring or a partially unsaturated heterocyclic ring        having 1-3 heteroatoms independently selected from nitrogen,        oxygen, and sulfur;    -   R^(z) is hydrogen, —R², —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR,        —C(O)R, —N(R)₂, —NH[Ar], —OR, or —S(O)₂N(R)₂;    -   [Ar] is phenyl or a 5-6 membered heteroaromatic ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, wherein said [Ar] is substituted by m instances of R;    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   m is 0-4; and    -   n is 0-4;        as defined and described in WO 2017/004134, the entirety of each        of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK inhibitor

thereby forming a compound of formula I-rr-1, I-rr-2, or I-rr-3:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   R is aliphatic, heteroaliphatic, heteroaryl, aryl, halo, amide        or CN;    -   R¹ is H, aliphatic or heteroaliphatic;    -   or R and R¹, together with the atoms to which they are attached,        form a heterocyclyl ring;    -   R² is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl,        amide, heterocyclyl or araliphatic;    -   each R³ independently is H, aliphatic, halogen, heteroaliphatic,        —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl,        hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide,        amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl,        alkylphosphate, or alkylphosphonate;    -   y is from 1 to 6;        as defined and described in WO 2016/172560 and US 2016/0311839,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ss-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:

-   -   A is

-   -   X is N or C—R⁷;    -   R is hydrogen, R¹, halogen, cyano, nitro, —OR¹, —C(═O)—R¹,        —C(═O)O—R¹, —C(═O)NR¹¹—R¹, —S(═O)₂—R¹, —NR¹¹C(═O)—R¹,        —NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)O—R¹, —NR¹¹S(═O)₂R¹ or —NR¹¹R¹¹;    -   R¹ is C₁₋₆ alkyl substituted with 0-4 R^(1a), C₁₋₆ haloalkyl,        C₂₋₆ alkenyl substituted with 0-3 R^(1a), C₂₋₆ alkynyl        substituted with 0-3 R^(1a), C₃₋₁₀ cycloalkyl substituted with        0-3 R^(1a), C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10        membered heterocycle containing 1-4 heteroatoms selected from N,        O, and S, substituted with 0-3 R^(1a), or a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-3 R^(1a);    -   R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NRC(O)OR^(c), —NRC(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹,        —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl        substituted with 0-2 R^(a), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14        membered carbocycle substituted with 0-3 R^(a), or        —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-3 R^(a);    -   R² is C₆₋₁₀ aryl substituted with 0-4 R^(2a), a 5-10 membered        heterocycle containing 1-4 heteroatoms selected from N, O, and        S, substituted with 1-4 R^(2a), or a 5-10 membered heteroaryl        containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-4 R^(2a);    -   R^(2a) at each occurrence is independently selected from        hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),        —(CH₂)_(r)OC(O)R^(b), —(CH₂)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)_(r)NRC(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),        —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R,        —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a),        C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted        with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p) substituted with 0-2 R^(a);    -   R³ is C₁₋₆ alkyl substituted with 0-3 R^(3a), C₁₋₆ haloalkyl,        C₂₋₆ alkenyl substituted with 0-3 R^(3a), C₂₋₆ alkynyl        substituted with 0-3 R^(3a), C₃₋₁₀ cycloalkyl substituted with        0-3 R^(3a), C₆₋₁₀ aryl substituted with 0-3 R^(3a), a 5-10        membered heterocyclyl containing 1-4 heteroatoms selected from        N, O, and S, substituted with 0-3 R^(3a) or a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-3 R^(3a);    -   R^(3a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-1 R^(a);    -   R⁴ and R⁵ are independently selected from hydrogen, C₁₋₄ alkyl        substituted with 0-1 R^(f), (CH₂)-phenyl substituted with 0-3        R^(d), and a —(CH₂)-5-7 membered heterocycle comprising carbon        atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);    -   R⁶ and R⁷ are independently at each occurrence is selected from        hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),        —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)NR^(b)C(O)R, —(CH₂)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R, —S(O)₂R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-3 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-3 R^(a), provided R⁶ and R⁷ are        not both hydrogen;    -   R¹¹ at each occurrence is independently hydrogen, R^(c), C₁₋₄        alkyl substituted with 0-1 R, CH₂-phenyl substituted with 0-3        R^(d), or —(CH₂)-5-7 membered heterocycle comprising carbon        atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p)        substituted with 0-3 R^(d); or    -   R¹¹ and along with another R¹¹, R¹, or R² on the same nitrogen        atom may join to form an optionally substituted heterocycle;    -   R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NRC(O)NR¹¹R¹¹, —(O)_(p)NR¹¹R¹¹,        —NR^(b)(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl        substituted with 0-1 R^(f), C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14        membered carbocycle, or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p); or two R^(a) on adjacent or        the same carbon atom form a cyclic acetal of the formula        —O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1 or        2;    -   R^(b) is hydrogen, R^(c), C₁₋₆ alkyl substituted with 0-2 R^(d),        C₁₋₆haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or        (CH₂)_(r)-phenyl substituted with 0-3 R^(d); R^(c) is C₁₋₆ alkyl        substituted with 0-1 R^(f), C₃₋₆ cycloalkyl, or (CH₂)_(r)-phenyl        substituted with 0-3 R^(f);    -   R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),        —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(c), C₁₋₆        alkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(e) is selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,        and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(f) is hydrogen, halo, NH₂, OH, or O(C₁₋₆alkyl);    -   p is 0, 1, or 2;    -   r is 0, 1, 2, 3, or 4; and    -   m is 0, 1, or 2;        as defined and described in WO 2013/106612 and US 2015/0011532,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-tt-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   A is a triazole optionally substituted by 0-2 R;    -   X is N or C—R⁷;    -   R is hydrogen, R′, halogen, cyano, nitro, —OR¹, —C(═O)—R¹,        —C(═O)O—R¹, —C(═O)NR¹¹—R¹, —S(═O)₂—R¹, —NR¹¹C(═O)—R′,        —NR¹¹C(═O)NR¹¹R¹, —NR¹¹C(═O)O—R′, —NR¹¹S(═O)₂R¹ or —NR¹¹R¹;    -   R¹ is C₁₋₆ alkyl substituted with 0-4 R^(1a), C₁₋₆ haloalkyl,        C₂₋₆ alkenyl substituted with 0-3 R^(1a), C₂₋₆ alkynyl        substituted with 0-3 R^(1a), C₃₋₁₀cycloalkyl substituted with        0-3 R^(1a), C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10        membered heterocycle containing 1-4 heteroatoms selected from N,        O, and S, substituted with 0-3 R^(1a), or a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-3 R^(1a);    -   R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NRS(O)_(p)R^(c), —S(C)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-3 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-3 R^(a);    -   R² is C₆₋₁₀ aryl substituted with 0-4 R^(2a), a 5-10 membered        heterocycle containing 1-4 heteroatoms selected from N, O, and        S, substituted with 1-4 R^(2a), or a 5-10 membered heteroaryl        containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-4 R^(2a);    -   R^(2a) at each occurrence is independently selected from        hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),        —(CH₂)_(r)OC(O)R^(b), —(CH₂)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)_(r)NR^(b)C(O)R, —(CH₂)_(r)NR^(b)C(O)OR^(c),        —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),        —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a),        C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted        with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p) substituted with 0-2 R^(a);    -   R³ is C₁₋₆ alkyl substituted with 0-3 R^(3a), C₁₋₆ haloalkyl,        C₂₋₆ alkenyl substituted with 0-3 R^(3a), C₂₋₆ alkynyl        substituted with 0-3 R^(3a), C₃₋₁₀cycloalkyl substituted with        0-3 R^(3a), C₆₋₁₀ aryl substituted with 0-3 R^(3a), a 5-10        membered heterocyclyl containing 1-4 heteroatoms selected from        N, O, and S, substituted with 0-3 R^(3′) or a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-3 R^(3a);    -   R^(3a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-1 R^(a);    -   R⁴ and R⁵ are independently selected from hydrogen, C₁₋₄ alkyl        substituted with 0-1 R^(f), (CH₂)-phenyl substituted with 0-3        R^(d), and a —(CH₂)-5-7 membered heterocycle comprising carbon        atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);    -   R⁶ and R⁷ are independently at each occurrence is selected from        hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),        —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)_(r)NR^(b)C(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),        —NR^(b)C(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),        —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a),        C₁₋₆haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted        with 0-3 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p) substituted with 0-3 R^(a),        provided R⁶ and R⁷ are not both hydrogen;    -   R¹¹ at each occurrence is independently hydrogen, R^(e), C₁₋₄        alkyl substituted with 0-1 R^(f), CH₂-phenyl substituted with        0-3 R^(d), or —(CH₂)-5-7 membered heterocycle comprising carbon        atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p)        substituted with 0-3 R^(d); or    -   R¹¹ and along with another R¹¹, R¹, or R² on the same nitrogen        atom may join to form an optionally substituted heterocycle;    -   R^(a) is hydrogen, F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle, or —(CH₂)_(r)-5-7 membered        heterocycle or heteroaryl, each comprising carbon atoms and 1-4        heteroatoms selected from N, O, and S(O)_(p); or two R^(a) on        adjacent or the same carbon atom form a cyclic acetal of the        formula —O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected        from 1 or 2;    -   R^(b) is hydrogen, R^(c), C₁₋₆ alkyl substituted with 0-2 R^(d),        C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl substituted with 0-2 R^(d), or        (CH₂)_(r)-phenyl substituted with 0-3 R^(d);    -   R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl,        or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(e),        —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(e), —NR^(e)C(O)OR^(e), C₁₋₆        alkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(e) is selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,        and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(f) is hydrogen, halo, NH₂, OH, or O(C₁₋₆alkyl);    -   p is 0, 1, or 2;    -   r is 0, 1, 2, 3, or 4; and    -   m is 0, 1, or 2;        as defined and described in WO 2013/106614 and US 2015/0045347,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-uu-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is N or C—R⁷;    -   R is R¹, halogen, cyano, nitro, —O—R¹, —C(═O)—R¹, —C(═O)O—R¹,        —C(═O)NR¹—R¹, —S(═O)₂—R¹, —NR¹¹C(═O)—R¹, —NR¹¹C(═O)NR¹¹—R¹,        —NR¹¹C(═O)O—R¹, —NR¹¹S(O)₂—R¹, or —NR¹¹—R¹;    -   R¹ is C₁₋₆ alkyl substituted with 0-4 R^(1a), C₁₋₆ haloalkyl,        C₂₋₆ alkenyl substituted with 0-3 R^(1a), C₂₋₆ alkynyl        substituted with 0-3 R^(1a), C₃₋₁₀cycloalkyl substituted with        0-3 R^(1a), C₆₋₁₀ aryl substituted with 0-3 R^(1a), a 5-10        membered heterocycle containing 1-4 heteroatoms selected from N,        O, and S, substituted with 0-3 R^(1a), a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-3 R^(1a);    -   R^(1a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-3 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle comprising carbon atoms        and 1-4 heteroatoms selected from N, O, and S(O)_(p) substituted        with 0-3 R^(a);    -   R² is C₆₋₁₀ aryl substituted with 0-4 R^(2a), a 5-10 membered        heterocycle containing 1-4 heteroatoms selected from N, O, and        S, substituted with 0-4 R^(2a), a 5-10 membered heteroaryl        containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-4 R^(2a);    -   R^(2a) at each occurrence is independently selected from        hydrogen, ═O, halo, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)CO)OR_(b),        —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)_(r)NRC(O)R^(c), —(CH₂)_(r)NR^(b)C(O)OR^(c),        —NRC(O)NR¹¹R¹¹, —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c),        —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(a),        C₁₋₆ haloalkyl, —(CH₂)_(r)-3-14 membered carbocycle substituted        with 0-1 R^(a), or —(CH₂)_(r)-5-7 membered heterocycle or        heteroaryl, each comprising carbon atoms and 1-4 heteroatoms        selected from N, O, and S(O)_(p) substituted with 0-2 R^(a);    -   R³ is C₁₋₆ alkyl substituted with 0-3 R^(3a), C₁₋₆ haloalkyl,        C₂₋₆ alkenyl substituted with 0-3 R^(3a), C₂₋₆ alkynyl        substituted with 0-3 R^(3a), C₃₋₁₀ocycloalkyl substituted with        0-3 R^(3a), C₆₋₁₀ aryl substituted with 0-3 R^(3a), a 5-10        membered heterocycle containing 1-4 heteroatoms selected from N,        O, and S, substituted with 0-3 R^(3a), or a 5-10 membered        heteroaryl containing 1-4 heteroatoms selected from N, O, and S,        substituted with 0-3 R^(3a);    -   R^(3a) is hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆ haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-1 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-1 R^(a);    -   R⁴ and R⁵ are independently selected from hydrogen, C₁₋₄ alkyl        substituted with 0-1 R^(f), (CH₂)-phenyl substituted with 0-3        R^(d), and a —(CH₂)-5-7 membered heterocycle comprising carbon        atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);    -   R⁶ and R⁷ are independently at each occurrence is selected from        hydrogen, ═O, F, Cl, Br, OCF₃, CN, NO₂, —(CH₂)_(r)OR^(b),        —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b), —(CH₂)_(r)C(O)OR^(b),        —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹, —(CH₂)_(r)C(O)NR¹¹R¹¹,        —(CH₂)_(r)NRC(O)R, —(CH₂)_(r)NRC(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-2 R^(a), C₁₋₆haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle substituted with 0-3 R^(a),        or —(CH₂)_(r)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-3 R^(a), provided R⁶ and R⁷ are        not both hydrogen;    -   R¹¹ at each occurrence is independently R^(c), C₁₋₄ alkyl        substituted with 0-1 R^(f), CH₂-phenyl substituted with 0-3        R^(d), or —(CH₂)-5-7 membered heterocycle or heteroaryl, each        comprising carbon atoms and 1-4 heteroatoms selected from N, O,        and S(O)_(p) substituted with 0-3 R^(d); alternatively, R¹¹ and        along with another R¹¹, R¹, or R² on the same nitrogen atom may        join to form an optionally substituted azetidinyl, pyrrolidinyl,        piperidinyl, morpholinyl, or 4-(C₁₋₆ alkyl)piperazinyl;    -   R^(a) is R^(d), F, Cl, Br, OCF₃, CF₃, CHF₂, CN, NO₂,        —(CH₂)_(r)OR^(b), —(CH₂)_(r)SR^(b), —(CH₂)_(r)C(O)R^(b),        —(CH₂)_(r)C(O)OR^(b), —(CH₂)_(r)OC(O)R^(b), —(CH₂)_(r)NR¹¹R¹¹,        —(CH₂)_(r)C(O)NR¹¹R¹¹, —(CH₂)_(r)NR^(b)C(O)R^(c),        —(CH₂)_(r)NR^(b)C(O)OR^(c), —NR^(b)C(O)NR¹¹R¹¹,        —S(O)_(p)NR¹¹R¹¹, —NR^(b)(O)_(p)R^(c), —S(O)₂R^(c), —S(O)₂R^(c),        C₁₋₆ alkyl substituted with 0-1 R^(f), C₁₋₆ haloalkyl,        —(CH₂)_(r)-3-14 membered carbocycle, or —(CH₂)_(r)-5-7 membered        heterocycle comprising carbon atoms and 1-4 heteroatoms selected        from N, O, and S(O)_(p); alternatively two R^(a) on adjacent or        the same carbon atom form a cyclic acetal of the formula        —O—(CH₂)_(n)—O—, or —O—CF₂—O—, wherein n is selected from 1 or        2;    -   R^(b) is R^(c), C₁₋₆ alkyl substituted with 0-2 R^(d), C₁₋₆        haloalkyl, C₃₋₆cycloalkyl substituted with 0-2 R^(d), or        (CH₂)_(r)-phenyl substituted with 0-3 R^(d);    -   R^(c) is C₁₋₆ alkyl substituted with 0-1 R^(f), C₃₋₆ cycloalkyl,        or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(d) is hydrogen, F, Cl, Br, OCF₃, CF₃, CN, NO₂, —OR^(c),        —(CH₂)_(r)C(O)R^(c), —NR^(e)R^(f), —NR^(e)C(O)OR^(c), C₁₋₆        alkyl, or (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(e) is selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,        and (CH₂)_(r)-phenyl substituted with 0-3 R^(f);    -   R^(f) is hydrogen, halo, NH₂, OH, or O(C₁₋₆alkyl);    -   p is 0, 1, or 2;    -   r is 0, 1, 2, 3, or 4; and    -   m is 0, 1, or 2;        as defined and described in WO 2013/106641 and US 2015/0018344,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor or

thereby forming a compound of formula I-vv-1 or I-vv-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   R¹ is:        -   (a) C₂₋₃ hydroxyalkyl substituted with zero to 4 R^(1a)            wherein R^(1a) is independently selected from F, Cl, —OH,            —CHF₂, —CN, —CF₃, —OCH₃, and cyclopropyl;    -   (b) C₁₋₃ alkyl substituted with —O(C₁₋₃ alkyl) and zero to 4        R^(1a) wherein R^(1a) is independently selected from F, Cl, —OH,        —CHF₂, —CN, —CF₃, and cyclopropyl;    -   (c) C₄₋₈ alkyl substituted with zero to 7 R^(1a) wherein R^(1a)        is independently selected from F, Cl, —OH, —CHF₂, —CF₃,        —CN—OCH₃, cyclopropyl, and —OP(O)(OH)₂;    -   (d) —(CH₂)₂₋₄NHC(O)(C₁₋₆ alkyl),        —(CH₂)₂CH(CH₃)NHC(O)(C₁₋₆alkyl),        —(CH₂)₂CH(CH₃)NHC(O)(CH₂)₀₋₁NH(C₁₋₆ alkyl), or        —(CH₂)₂CH(CH₃)NHC(O)(CH₂)₀₋₁N(C₁₋₄ alkyl)₂;        -   (e) cyclohexyl substituted with zero to 2 substituents            independently selected from —OH, —OCH₃, C₁₋₆ alkyl,            C₁₋₆hydroxyalkyl, —C(O)NH₂, —C(O)NH(C₁₋₃ alkyl),            —C(O)NH(C₁₋₆ hydroxyalkyl), —C(O)NH(C₃₋₆ cycloalkyl),            —C(O)NH(C₃₋₆ fluoro cycloalkyl), —NHC(O)(C₁₋₃ alkyl),            —NHC(O)O(C₁₋₃ alkyl), —NHS(O)₂CH₃, —S(O)₂NH₂, —S(O)₂(C₁₋₃            alkyl), —S(C₁₋₃ alkyl), thiazolyl, methyl pyrazolyl, and            C₁₋₃ alkyl substituted with —OH and cyclopropyl;        -   (f) —(CH₂)₂(phenyl) wherein said phenyl is substituted with            —C(O)NH₂, —C(O)NH(C₁. 3 alkyl), or —S(O)₂NH₂; or        -   (g) piperidinyl substituted with —C(O)(C₁₋₃ alkyl);    -   R² is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazolyl,        thiazolyl, or triazolyl, each substituted with zero to 2        substituents independently selected from F, Cl, —OH, —CN, C₁₋₃        alkyl, —CH₂C(O)OCH₃, —O(C₁₋₃alkyl), —NH₂, —NH(C₁₋₃ alkyl),        —NH(cyclopropyl), —C(O)NH₂, —NHC(O)(C₁₋₃ alkyl),        —NH(tetrahydropyranyl), hydroxypyrrolidinyl, ═O,        —O(piperidinyl), and pyridinyl; and    -   R³ is:        -   (a) C₁₋₆ alkyl substituted with zero to 4 substituents            independently selected from F, —OH, —CH₃, —CF₃, and            C₃₋₆cycloalkyl;        -   (b) C₃₋₆ cycloalkyl substituted with zero to 2 substituents            independently selected from F, —OH, C₁₋₃ hydroxyalkyl, —CH₃,            —CF₂H, —NH₂, and —C(O)OCH₂CH₃;        -   (c) oxetanyl, tetrahydropyranyl, or fluoro            tetrahydropyranyl;        -   (d) phenyl substituted with zero to 2 substituents            independently selected from —OH, —CN, —O(C₁₋₃ alkyl), C₁₋₃            hydroxyalkyl, —C(O)NH₂, —S(O)₂NH₂, —NHS(O)₂(C₁₋₃ alkyl),            pyrazolyl, imidazolyl, and methyl tetrazolyl; or        -   (e)

as defined and described in WO 2014/074675 and US 2015/0284382, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-xx-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   R¹ is an optionally substituted aromatic heterocyclic group or        an optionally substituted C₆₋₁₄ aryl group;    -   R² is a hydrogen atom or a substituent; R³ and R⁴ are        independently a hydrogen atom or a substituent, or R³ and R⁴ in        combination optionally form an optionally substituted ring;    -   R⁵ and R⁶ are independently a hydrogen atom or a substituent, or        R⁵ and R⁶ in combination optionally form an optionally        substituted ring;    -   X is CR⁷R⁸, NR⁹, O or S;    -   R⁷ and R⁸ are independently a hydrogen atom or a substituent, or        R⁷ and R⁸ in combination optionally form an optionally        substituted ring; and    -   R⁹ is a hydrogen atom or a substituent;        as defined and described in WO 2015/068856 and US 2015/0133451,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein LBM is an E3 ubiquitin ligase (IAP) binding moiety

thereby forming a compound of formula I-yy-1

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein thevariable R is as defined and described in Ohoka, N. et al. (2017). InVivo Knockdown of Pathogenic Proteins via Specific and NongeneticInhibitor of Apoptosis Protein (IAP)-dependent Protein Erasers(SNIPERs). Journal of Biological Chemistry, 292(11), 4556-4570, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-zz-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   R¹ denotes absent, A or Q-Het,    -   Z is

-   -   wherein    -   X denotes O, S or N,    -   Y denotes C or N,    -   T denotes C or N, or    -   Z denotes a pyridine or a pyridazine group,    -   R^(a) is absent, OR³, CF₃, Hal, or NO₂,    -   R^(b) is absent, A, or COHet,    -   R² denotes H, Het, Q-Het, Cyc, A or OA,    -   each Het is independently a 4-9 membered monocyclic ring or a        fused, spiro or bridged bicyclic ring, which is saturated,        unsaturated, or aromatic, which contains 1 to 3 heteroatoms        independently selected from N, O, and S, and a group CO, SO or        SO₂, and wherein 1 or 2 H atoms may be replaced by A, OA, COA,        CN, Hal, NO₂, OR³, SOA and/or SO₂A,    -   Cyc denotes a 4-8 saturated carbocyclic ring optionally        containing a group SO, SO₂, or CO, and optionally substituted        once or twice by a group selected from CO(NR³)₂, COHet, OR³,        Het¹, A, CH₂Het¹, NH₂, NHCOA, OCH₂Cyc¹, SO₂A and -SA(═NH)(═O),    -   each Q is independently a linear or branched alkylene, having 1        to 6 carbon atoms wherein 1-5 H atoms may be replaced by a group        independently selected from OR³, Hal, and N(R³)₂, and wherein 1        or 2 CH₂ groups may be replaced by a group independently        selected from CO, SO, SO₂ and NR³, or Q denotes a 4-8-membered        bivalent heterocyclic ring, which is saturated, unsaturated or        aromatic and which contains 1 to 3 heteroatoms independently        selected from N, O and S,    -   each A is independently a linear or branched alkyl having 1 to        10 carbon atoms wherein 1 to 7 H atoms may be replaced by a        group independently selected from —OR³, Hal, NHSO₂A, SO₂A, SOA,        and N(R³)₂, and wherein 1, 2 or 3 non-adjacent —CH₂— groups may        be replaced by a group independently selected from —CO—, NR³ and        —O—,    -   each Hal is independently F, Cl, Br or I,    -   each R³ is independently H or C₁-C₆-alkyl wherein 1 H atom may        be replaced by a group selected from OH, O—C₁-C₆-alkyl, and Hal,    -   each Het¹ is independently a five- or six membered saturated        monocyclic heterocycle which contains 1-3 N- and/or O-atoms,        which optionally is monosubstituted by A,    -   Cyc¹ denotes cycloalkyl with 3-7 atoms; as defined and described        in WO 2014/008992 and US 2015/0141396, the entirety of each of        which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-aaa-1

or a pharmaceutically acceptable salt thereof, wherein L and LBM are asdefined above and described in embodiments herein, and wherein:

-   -   Ring A is a monocyclic heteroaryl;    -   R¹ is one to three optionally substituted with R¹⁰ monocyclic or        bicyclic heteroaryl;    -   R² is, —C(O)NH₂, —C(O)NH—R⁰, —C(O)NH—R⁰⁰—OH, —C(O)NH—R⁰⁰—OR⁰,        —C(O)N(R⁰)₂, —C(O)NH— cycloalkyl, —C(O)NH-heterocycloalkyl,        —C(O)NH-(pyrazolyl optionally substituted with R⁰), —C(O)—R⁰,        —C(O)— cycloalkyl, —S(O)₂NH₂, —S(O)₂NH—R⁰, —S(O)₂NH-cycloalkyl,        —R⁰—OH, —R⁰⁰—OR^(c), —R⁰⁰-(morpholin-4-yl) phenyl, oxadiazolyl,        or tetrazolyl optionally substituted with R^(c), wherein        oxadiazolyl in R² is, R⁰, R⁰⁰—OH or may be substituted with        R⁰—OR⁰;    -   R³ is, H, R⁰, halogeno-lower alkyl, cycloalkyl,        heterocycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl,        —C(O)N(R⁰)₂, —R⁰⁰-cycloalkyl, —R⁰⁰-heterocycloalkyl,        —R⁰⁰-phenyl, —R⁰⁰—OH or a —R⁰⁰—OR^(c), wherein the cycloalkyl in        R³, heterocycloalkyl, phenyl and pyridyl, R⁰, halogen, —C(O)OR⁰,        —C(O)—R⁰, —OH, —OR⁰, —S(O)₂—R⁰, —O-halogeno-lower alkyl,        —OR⁰⁰-(morpholin-4-yl), —R⁰⁰—OH, —R⁰⁰—OR⁰, morpholin-4-yl or,        —R⁰⁰-(morpholin-4-yl) may be substituted;    -   R¹⁰ may be the same or different from each other, R^(c),        halogen, halogeno-lower alkyl, cycloalkyl, —OR⁰, optionally        substituted amino, —O-halogeno-lower alkyl, —R⁰⁰—OH, —R⁰⁰—OR⁰        or, —R⁰⁰— is optionally amino substituted,    -   R⁰ is the same or different from each other, lower alkyl,    -   R⁰⁰ are identical or different from each other, it is a lower        alkylene; as defined and described in WO 2011/043371, the        entirety of which is herein incorporated by reference.

In some embodiments, the compound of formula I-aaa-1 above is providedas a compound of formula I-aaa-2, I-aaa-3, or I-aaa-4:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of LBM, L, R¹, R², R³, and R¹⁰ is as defined above.

In some embodiments, In certain embodiments, the present inventionprovides a compound of

Formula I, wherein IRAK is an IRAK4 inhibitor;thereby forming a compound of formula I-bbb-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is selected from O, S, and NH;    -   A is selected from aryl or heteroaryl;    -   R at each occurrence is independently selected from hydrogen,        cyano, halo, hydroxy, —NO₂, —NR³R⁴, optionally substituted        alkyl, optionally substituted aryl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl or        optionally substituted heteroaryl; wherein the optional        substituent, in each occurrence, is independently selected from        halo, alkyl, haloalkyl, cyano, —NR⁵R⁶ or —COOR⁷;    -   R¹ at each occurrence is independently selected from hydrogen,        halogen, alkyl, aryl, heterocycloalkyl, heterocycloalkylalkyi,        heteroaryl, Y-arylalkyl or —Y-cycloalkyl; wherein cycloalkyi,        aryl, heterocycloalkyl, heterocycloalkylalkyi, heteroaryl and        arylalkyl can be optionally substituted with hydroxy, alkyl,        haloalkyl, cyano or halo;    -   Y is selected from direct bond, O, —C(O)— or NR⁷;    -   R² at each occurence is independently selected from hydrogen,        carboxy, cyano, hydroxy, hydroxyalkyl, alkyl, aryl, heteroaryl,        —SO²R⁵ or oxo;    -   R³ and R⁴ are independently selected from hydrogen,        hydroxyalkyl, aminoalkyl, optionally substituted alkyl,        optionally substituted heterocyclyl, optionally substituted        aryl; wherein the optional substituent, in each occurrence, is        independently selected from halo, haloalkyl or —COOR⁷;    -   R⁵ and R⁶ are independently selected from hydrogen, alkyl, COR⁷        or —COOR⁷;    -   R⁷ at each occurrence is independently selected from hydrogen or        alkyl; and    -   m, n and p are selected from 1, 2 or 3;        as defined and described in WO 2013/042137, the entirety of        which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ccc-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring Z₁ is an optionally substituted heteroaryl;    -   Ring Z₂ is an optionally substituted heterocycloalkyl,        optionally substituted heteroaryl or a direct bond;    -   R₁ is alkyl, cyano, —NR_(a)R_(b) or optionally substituted        groups selected from cycloalkyl, aryl or heterocyclyl; wherein        the substituent, at each occurrence, independently is alkyl,        alkoxy, halogen, hydroxyl, hydroxyalkyl, amino, aminoalkyl,        nitro, cyano, haloalkyl, haloalkoxy, —OCO—CH₂—O-alkyl,        —OP(O)(O-alkyl)₂ or —CH₂—OP(O)(O-alkyl)₂;    -   R₂, at each occurrence, independently is an optionally        substituted group selected from alkyl or cycloalkyl; wherein the        substituent, at each occurrence, is independently halogen,        alkoxy, hydroxyl, hydroxyalkyl, haloalkyl or haloalkoxy;    -   R₃, at each occurrence, independently is hydrogen, halogen,        alkyl, haloalkyl, haloalkoxy, alkoxy, —NR_(a)R_(b), hydroxyl or        hydroxyalkyl;    -   R_(a) is hydrogen or alkyl;    -   R_(b) is hydrogen, alkyl, acyl, hydroxyalkyl, —SO₂-alkyl or        optionally substituted cycloalkyl;    -   m and n are independently 1 or 2;        as defined and described in WO 2015/104662 and US 2016/0326151,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ddd-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X₁ and X₃ independently are CH or N; X₂ is CR₂ or N; provided        one and not more than one of X₁, X₂ or X₃ is N;    -   A is O or S;    -   Y is —CH₂— or O;    -   Ring Z is aryl or heterocyclyl;    -   R₁, at each occurrence, is independently halo or optionally        substituted heterocyclyl; wherein the substituent is alkyl,        alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkyl or        —NR_(a)R_(b);    -   R₂ is hydrogen, optionally substituted cycloalkyl, optionally        substituted aryl, optionally substituted heterocyclyl or        —NR_(a)R_(b); wherein the substituent is alkyl, amino, halo or        hydroxyl;    -   R₃, at each occurrence, is alkyl or hydroxyl;    -   R_(a) and R_(b) are independently hydrogen, alkyl, acyl or        heterocyclyl;    -   m and n are independently 0, 1 or 2;    -   p is 0 or 1;        as defined and described in WO 2015/104688 and US 2016/0340366,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-eee-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Z₁ is optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heterocyclyl or is    -   absent;    -   Z₂ is optionally substituted cycloalkyl, aryl or heterocyclyl;        R₁ is hydrogen, optionally substituted alkyl, amino, halogen,        cyano, optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heterocyclyl, optionally        substituted arylalkyl or optionally substituted        heterocyclylalkyl;    -   R₂ at each occurrence is hydrogen, halogen, amino, optionally        substituted alkyl, optionally substituted cycloalkyl, optionally        substituted aryl, optionally substituted heterocyclyl,        optionally substituted arylalkyl or optionally substituted        heterocyclylalkyl;    -   R₃ at each occurrence is hydroxy, halogen, optionally        substituted alkyl, optionally substituted alkoxy, optionally        substituted cycloalkyl or —NR_(a)R_(b);    -   R_(a) and R_(b), independently for each occurrence, are        hydrogen, optionally substituted alkyl, optionally substituted        acyl, optionally substituted cycloalkyl, optionally substituted        aryl, optionally substituted heterocyclyl, optionally        substituted arylalkyl or optionally substituted        heterocyclylalkyl;    -   m at each occurrence, is 0, 1 or 2; and    -   n at each occurrence, is 0, 1, or 2;        as defined and described in WO 2015/193846 and US 2017/0152263,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-fff-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein R⁰ represents hydrogen or C₁-C₄-alkyl, where the        C₁-C₄-alkyl radical may optionally be mono- or polysubstituted        by identical or different radicals from the group consisting of        hydroxy and halogen;    -   R¹ represents hydrogen, halogen, cyano, C(═O)OH, C(═O)OR^(a),        C(═O)NH₂, C(═O)N(H)R^(a), C(═O)N(R^(a))R^(b), C(═O)R^(d),        hydroxy or C₁-C₆-alkyl, where the C₁-C₆-alkyl radical is        optionally mono- or polysubstituted by identical or different        radicals from the group consisting of hydroxy, halogen, cyano,        C(═O)OH, C(═O)OR^(a), S(═O)₂—C₁-C₆-alkyl, NH₂, NHR^(a),        N(R^(a))R^(b), C₁-C₆-alkoxy which is optionally mono- or        polysubstituted by identical or different radicals from the        group consisting of halogen, C₃-C₈-cycloalkoxy which is        optionally mono- or polysubstituted by identical or different        radicals from the group consisting of halogen, heterocycloalkyl        which is optionally mono- or polysubstituted by identical or        different radicals from the group consisting of R^(c), or        represents C₁-C₆-alkoxy, where the C₁-C₆-alkoxy radical may        optionally be mono- or polysubstituted by identical or different        radicals from the group consisting of hydroxy, halogen, cyano,        C(═O)OH, C(═O)OR^(a), S(═O)₂—C₁-C₆-alkyl, NH₂, NHR^(a),        N(R^(a))R^(b), C₃-C₈-cycloalkyl which is optionally mono- or        polysubstituted by identical or different radicals from the        group consisting of halogen, C₁-C₆-alkoxy which is optionally        mono- or polysubstituted by identical or different radicals from        the group consisting of halogen, C₃-C₈-cycloalkoxy which is        optionally mono- or polysubstituted by identical or different        radicals from the group consisting of halogen, heterocycloalkyl        which is optionally mono- or polysubstituted by identical or        different radicals from the group consisting of R^(c), aryl        which is optionally mono- or polysubstituted by identical or        different radicals from the group consisting of R^(c), or 5- or        6-membered heteroaryl which is optionally mono- or        polysubstituted by identical or different radicals from the        group consisting of R^(c),        -   or represents C₃-C₈-cycloalkoxy or heterocycloalkoxy which            may optionally be mono- or polysubstituted by identical or            different radicals from the group consisting of hydroxy,            halogen, cyano and C₁-C₆-alkyl,        -   or represents aryloxy or 5- or 6-membered heteroaryloxy in            which aryloxy and 5- or 6-membered heteroaryloxy may            optionally be mono- or polysubstituted by identical or            different radicals from the group consisting of hydroxy,            halogen, cyano, C(═O)OH, C(═O)OR^(a), C₁-C₆-alkyl and            C₁-C₆-alkoxy,        -   or represents C₃-C₈-cycloalkyl or heterocycloalkyl which may            optionally be mono- or polysubstituted by identical or            different radicals from the group consisting of hydroxy,            halogen, cyano and C₁-C₆-alkyl,        -   or represents C₂-C₆-alkenyl or C₂-C₆-alkynyl,        -   or represents aryl, 5- to 10-membered heteroaryl,            aryl-C₁-C₄-alkyl or 5- or 6-membered heteroaryl-C₁-C₄-alkyl,            where aryl and heteroaryl may optionally be mono- or            polysubstituted by identical or different radicals from the            group consisting of halogen, hydroxy, cyano, C(═O)OH,            C(═O)OR^(a), C₁-C₆-alkyl, C₃-C₈-cycloalkyl and C₁-C₆-alkoxy;    -   R^(a) represents C₁-C₆-alkyl, C₃-C₁₀-cycloalkyl,        heterocycloalkyl, aryl or heteroaryl, where alkyl, cycloalkyl,        heterocycloalkyl, aryl and heteroaryl may optionally be mono- or        polysubstituted by identical or different radicals from the        group consisting of halogen, hydroxy, cyano, C₁-C₃-alkyl,        C₁-C₃-alkoxy, heterocycloalkyl, —C(═O)O—C₁-C₆-alkyl and        S(═O)₂—C₁-C₆-alkyl;    -   R^(b) represents C₁-C₆-alkyl or C₃-C₁₀-cycloalkyl;        -   or R^(a) and R^(b) together with the nitrogen atom form a 5-            or 6-membered heterocycle which may optionally be mono- or            polysubstituted by identical or different radicals from the            group consisting of hydroxy, halogen, cyano, and            C₁-C₆-alkyl;    -   R^(c) represents hydroxy, halogen, cyano, C₁-C₃-alkyl or        C₁-C₃-alkoxy;    -   R^(d) represents hydrogen, C₁-C₆-alkyl or C₃-C₁₀-cycloalkyl;    -   R² represents hydrogen, C₁-C₆-alkyl or C₃-C₆-cycloalkyl;    -   R¹³ represents hydrogen or C₁-C₆-alkyl;    -   W represents 5-membered heteroaryl which contains one to three        heteroatoms selected from the group consisting of N, O and S and        may optionally be monosubstituted by R³ and optionally be mono-        or polysubstituted by identical or different radicals R⁴ or    -   W represents pyridyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl or        1,3,5-triazinyl which may optionally be monosubstituted by R³        and optionally be mono- or polysubstituted by identical or        different radicals R⁴;    -   R³ represents hydrogen, halogen, cyano, C(═O)R^(a), NH₂,        NHR^(a), N(R^(a))R^(b), N(H)C(═O)R^(a) or C₁-C₆-alkyl, where        C₁-C₆-alkyl may optionally be mono- or polysubstituted by        identical or different radicals from the group consisting of        hydroxy, halogen, cyano, C(═O)R^(a), C(═O)OH, C(═O)OR^(a),        S(═O)₂—C₁-C₆-alkyl, NH₂, NHR^(a), N(R^(a))R^(b), C₁-C₆-alkoxy,        C₃-C₆-cycloalkoxy,        -   where C₁-C₆-alkoxy and C₃-C₆-cycloalkoxy may optionally be            mono- or polysubstituted by identical or different halogen            radicals;        -   or C₁-C₆-alkyl is optionally mono- or polysubstituted by            identical or radicals from the group consisting of            C₃-C₆-cycloalkyl and heterocycloalkyl,        -   where C₃-C₆-cycloalkyl and heterocycloalkyl may optionally            be mono-, di- or trisubstituted by identical or different            radicals from the group consisting of halogen, cyano,            C₁-C₃-alkyl and C₁-C₃-alkoxy, or C₁-C₆-alkyl is optionally            mono- or polysubstituted by identical or different radicals            from the group consisting of aryl and 5- or 6-membered            heteroaryl,        -   where aryl and 5- or 6-membered heteroaryl may optionally be            mono-, di- or trisubstituted by identical or different            radicals from the group consisting of halogen, cyano,            C₁-C₃-alkyl and C₁-C₃-alkoxy,    -   or R³ represents C₁-C₆-alkoxy,        -   where C₁-C₆-alkoxy may optionally be mono- or            polysubstituted by identical or different radicals from the            group consisting of hydroxy, halogen, cyano, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₃-C₈-cycloalkyl,            C₁-C₄-alkoxy, C₃-C₈-cycloalkoxy, or represents            C₃-C₆-cycloalkyl, heterocycloalkyl or            C₅-C₁₁-spirocycloalkyl, where cycloalkyl, heterocycloalkyl            and spirocycloalkyl may optionally be mono- or            polysubstituted by identical or different radicals from the            group consisting of hydroxy, halogen, cyano, C(═O)R^(a),            C(═O)OH, C(═O)OR^(a), C₁-C₆-alkyl and C₁-C₄-alkoxy;        -   or represents aryl or 5- to 10-membered heteroaryl,        -   where aryl and heteroaryl may optionally be mono- or            polysubstituted by identical or different radicals from the            group consisting of halogen, hydroxy, cyano, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, NO₂, NH₂, NHR^(a), N(R^(a))R^(b),            N(H)C(═O)R^(a), C₃—C-cycloalkyl, C₁-C₃-alkoxy and            C₁-C₃-alkyl, where C₁-C₃-alkyl may optionally be mono- or            polysubstituted by identical or different halogen radicals;    -   R⁴ represents halogen, hydroxy, cyano or C₁-C₆-alkyl, where        C₁-C₆-alkyl may optionally be mono- or polysubstituted by        identical or different radicals from the group consisting of        halogen, C₁-C₆-alkoxy, where C₁-C₆-alkoxy may optionally be        mono- or polysubstituted by identical or different radicals from        the group consisting of halogen, C₂-C₆-alkenyl, C₂-C₆-alkynyl,        C₃-C₁₀-cycloalkyl, 3- to 10-membered heterocycloalkyl and aryl,        where aryl may optionally be mono- or polysubstituted by        identical or different radicals R;    -   or R⁴ represents aryl or heteroaryl which may optionally be        mono- or polysubstituted by identical or different radicals R;    -   or R⁴ represents C(═O)R^(a), C(═O)NH₂, C(═O)N(H)R^(a),        C(═O)N(R^(a))R^(b), C(═O)OR^(a), NH₂, NHR^(a), N(R^(a))R^(b),        N(H)C(═O)R^(a), N(R^(a))C(═O)R^(a), N(H)C(═O)NH₂,        N(H)C(═O)NHR^(a), N(H)C(═O)N(R^(a))R^(b), N(R^(a))C(═O)NH₂,        N(R^(a))C(═O)NHR^(a), N(R^(a))C(═O)N(R^(a))R^(b),        N(H)C(═O)OR^(a), N(R^(a))C(═O)OR^(a), NO₂, N(H)S(═O)R^(a),        N(R^(a))S(═O)R^(a), N(H)S(═O)₂R^(a), N(R^(a))S(═O)₂R^(a),        N═S(═O)(R^(a))R^(b), OC(═O)R^(a), OC(═O)NH₂, OC(═O)NHR^(a),        OC(═O)N(R^(a))R^(b), SH, SR^(a), S(═O)R^(a), S(═O)₂R^(a),        S(═O)₂NH₂, S(═O)₂NHR^(a), S(═O)₂N(R^(a))R^(b) or        S(═O)(═N—R^(a))R^(b);    -   R represents halogen, cyano, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₁₀-cycloalkyl, 3- to 10-membered        heterocycloalkyl, aryl, heteroaryl, C(═O)R^(a), C(═O)NH₂,        C(═O)N(H)R^(a), C(═O)N(R^(a))R^(b), C(═O)OR^(a), NH₂, NHR^(a),        N(R^(a))R^(b), N(H)C(═O)R^(a), N(R^(a))C(═O)R^(a), N(H)C(═O)NH₂,        N(H)C(═O)NHR^(a), N(H)C(═O)N(R^(a))R^(b), N(R^(a))C(═O)NH₂,        N(R^(a))C(═O)NHR^(a), N(R^(a))C(═O)N(R^(a))R^(b),        N(H)C(═O)OR^(a), N(R^(a))C(═O)OR^(a), NO₂, N(H)S(═O)R^(a),        N(R^(a))S(═O)R^(a), N(H)S(═O)₂R^(a), N(R^(a))S(═O)₂R^(a),        N═S(═O)(R^(a))R^(b), OH, C₁-C₆-alkoxy, OC(═O)R^(a), OC(═O)NH₂,        OC(═O)NHR^(a), OC(═O)N(R^(a))R^(b), SH, SR^(a), S(═O)R^(a),        S(═O)₂R^(a), S(═O)₂NH₂, S(═O)₂NHR^(a), S(═O)₂N(R^(a))R^(b) or        S(═O)(═NR^(a))R^(b);    -   n represents 0 or 1;    -   Y represents a group selected from:

-   -   where * represents the point of attachment of the group to the        remainder of the molecule;    -   R⁵ represents hydrogen, C₁-C₆-alkyl or C₃-C₁₀-cycloalkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy and            C₃-C₅-cycloalkyl;    -   R⁶ represents hydrogen or C₁-C₆-alkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C₃-C₁₀-cycloalkyl, C(═O)R^(a),            C(═O)OH, C(═O)OR^(a), S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b),            C₁-C₄-alkoxy and C₃-C₅-cycloalkoxy, or represents            C₃-C₁₀-cycloalkyl, where        -   C₃-C₁₀-cycloalkyl may optionally be mono- or polysubstituted            by identical or different radicals from the group consisting            of hydroxy, halogen, cyano and C₁-C₆-alkyl, where            C₁-C₆-alkyl may optionally be substituted by hydroxy, or            represents heterocycloalkyl, where heterocycloalkyl may            optionally be mono- or polysubstituted by identical or            different radicals from the group consisting of halogen,            cyano, C₁-C₃-alkyl and C₁-C₃-alkoxy, or represents aryl or            5- or 6-membered heteroaryl, where        -   aryl and 5- or 6-membered heteroaryl may optionally be mono-            or polysubstituted by identical or different radicals from            the group consisting of halogen, cyano, C₁-C₃-alkyl,            C₁-C₃-alkoxy, S(═O)₂NH₂, S(═O)₂NHR^(a) and            S(═O)₂N(R^(a))R^(b);    -   R^(7a) represents hydrogen, halogen, N(R^(a))R^(b), C₁-C₆-alkyl        or C₃-C₁₀-cycloalkyl, where C₁-C₆-alkyl may optionally be mono-        or polysubstituted by identical or different radicals from the        group consisting of hydroxy, halogen, cyano, C(═O)OH,        C(═O)OR^(a), S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,        C₃-C₈-cycloalkyl and heterocycloalkyl;    -   R^(7b) represents hydrogen, halogen or C₁-C₆-alkyl, where        C₁-C₆-alkyl may optionally be mono- or polysubstituted by        identical or different radicals from the group consisting of        hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),        S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,        C₃-C₅-cycloalkyl and heterocycloalkyl;    -   or R^(7a) and R^(7b) together with the carbon atom form        C₃-C₆-cycloalkyl which may optionally be mono- or        polysubstituted by identical or different radicals from the        group consisting of hydroxy, halogen, cyano and C₁-C₆-alkyl,    -   or R^(7a) and R^(7b) together represent an oxo group;    -   R^(7c) represents hydrogen, halogen, N(R^(a))R^(b), C₁-C₆-alkyl        or C₃-C₁₀-cycloalkyl, where C₁-C₆-alkyl may optionally be mono-        or polysubstituted by identical or different radicals from the        group consisting of hydroxy, halogen, cyano, C(═O)OH,        C(═O)OR^(a), S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,        C₃-C₈-cycloalkyl and heterocycloalkyl;    -   R^(7d) represents hydrogen, halogen or C₁-C₆-alkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,            C₃-C₈-cycloalkyl and heterocycloalkyl;    -   or R^(7c) and R^(7d) together with the carbon atom form        C₃-C₆-cycloalkyl which may optionally be mono- or        polysubstituted by identical or different radicals from the        group consisting of hydroxy, halogen, cyano and C₁-C₆-alkyl,    -   or R^(7c) and R^(7d) together represent an oxo group;    -   R^(8a) represents hydrogen, halogen, N(R^(a))R^(b), C₁-C₆-alkyl        or C₃-C₁₀-cycloalkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,            C₃-C₈-cycloalkyl and heterocycloalkyl;    -   R^(8b) represents hydrogen, halogen or C₁-C₆-alkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,            C₃-C₈-cycloalkyl and heterocycloalkyl;    -   or R^(8a) and R^(8b) together with the carbon atom form        C₃-C₆-cycloalkyl which may optionally be mono- or        polysubstituted by identical or different radicals from the        group consisting of hydroxy, halogen, cyano and C₁-C₆-alkyl,    -   R^(8c) represents hydrogen, halogen, N(R^(a))R^(b), C₁-C₆-alkyl        or C₃-C₁₀-cycloalkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,            C₃-C₈-cycloalkyl and heterocycloalkyl;    -   R^(8d) represents hydrogen, halogen or C₁-C₆-alkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy,            C₃-C₈-cycloalkyl and heterocycloalkyl;    -   or R^(8c) and R^(8d) together with the carbon atom form        C₃-C₆-cycloalkyl which may optionally be mono- or        polysubstituted by identical or different radicals from the        group consisting of hydroxy, halogen, cyano and C₁-C₆-alkyl,    -   or R^(8c) and R^(8d) together represent an oxo group;    -   represents 0, 1 or 2,    -   p represents 0, 1 or 2,    -   q represents 0, 1 or 2,    -   r represents 0, 1 or 2,    -   s represents 0, 1 or 2,    -   where o, p, q, r and s do not simultaneously represent 0;    -   Z represents a group selected from C(═O), CR⁹R¹⁰, NR¹¹, O, S,        S(═O) and S(═O)₂;    -   R⁹ represents hydrogen or C₁-C₆-alkyl,    -   R¹⁰ represents hydrogen, halogen, cyano, C(═O)R^(a), C(═O)OH,        C(═O)OR^(a), C(═O)NH₂, C(═O)N(H)R^(a), C(═O)N(R^(a))R^(b),        N(H)C(═O)R^(a), N(R^(b))C(═O)R^(a), S(═O)₂R^(a), hydroxy,        N(R^(a))R^(b) and C₁-C₆-alkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)R^(a), C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₁-C₄-alkoxy and            C₃-C₈-cycloalkoxy, or represents C₁-C₆-alkoxy, where            C₁-C₆-alkoxy may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a),            S(═O)₂—C₁-C₆-alkyl, N(R^(a))R^(b), C₃-C₈-cycloalkyl,            C₁-C₄-alkoxy, C₃-C₈-cycloalkoxy, heterocycloalkyl, aryl and            5- or 6-membered heteroaryl, where        -   aryl and 5- or 6-membered heteroaryl may optionally be mono-            or polysubstituted by identical or different radicals from            the group consisting of halogen, cyano, C₁-C₃-alkyl and            C₁-C₃-alkoxy, or represents aryloxy or 5- or 6-membered            heteroaryloxy in which aryloxy and 5- or 6-membered            heteroaryloxy may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)OH, C(═O)OR^(a), C₁-C₃-alkyl            and C₁-C₃-alkoxy,        -   or represents C₃-C₈-cycloalkyl,            C₃-C₈-cycloalkyl-C₁-C₄-alkyl, heterocycloalkyl or            heterocycloalkyl-C₁-C₄-alkyl, which may optionally be mono-            or polysubstituted by identical or different radicals from            the group consisting of hydroxy, halogen, cyano, C(═O)R^(a),            C(═O)OH, C(═O)OR^(a), C₁-C₆-alkyl and C₁-C₆-alkoxy, where        -   C₁-C₆-alkoxy may optionally be mono- or polysubstituted by            identical or different halogen radicals or an oxo group;        -   or represents C₂-C₆-alkenyl or C₂-C₆-alkynyl,        -   or represents aryl, 5- to 10-membered heteroaryl,            aryl-C₁-C₄-alkyl or 5- or 6-membered heteroaryl-C₁-C₄-alkyl,            where        -   aryl and heteroaryl may optionally be mono- or            polysubstituted by identical or different radicals from the            group consisting of halogen, hydroxy, cyano, C(═O)OH,            C(═O)OR^(a), NHR^(a), N(R^(a))R^(b), C₁-C₃-alkyl,            C₃-C₈-cycloalkyl and C₁-C₃-alkoxy;        -   or R⁹ and R¹⁰ together with the carbon atom form            C₃-C₈-cycloalkyl or a 4- to 6-membered heterocycle, where        -   the C₃-C₈-cycloalkyl radical or the 4- to 6-membered            heterocycle may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C₁-C₆-alkyl, C(═O)R^(a) and an oxo            group;    -   R¹¹ represents hydrogen, C(═O)R^(a), C(═O)OR^(a), C(═O)NH₂,        C(═O)N(H)R^(a), C(═O)N(R^(a))R^(b), S(═O)₂R^(a),        S(═O)₂N(R^(a))R^(b) or C₁-C₆-alkyl, where        -   C₁-C₆-alkyl may optionally be mono- or polysubstituted by            identical or different radicals from the group consisting of            hydroxy, halogen, cyano, C(═O)R^(a), C(═O)OR^(a), C(═O)NH₂,            C(═O)N(H)R^(a), C(═O)N(R^(a))R^(b), S(═O)₂—C₁-C₆-alkyl,            N(R^(a))R^(b), C₃-C₈-cycloalkyl, C₁-C₄-alkoxy and            C₃-C₈-cycloalkoxy, where        -   C₃-C₈-cycloalkyl, C₁-C₄-alkoxy and C₃-C₈-cycloalkoxy may            optionally be mono- or polysubstituted by identical or            different radicals from the group consisting of hydroxy and            halogen; or represents C₃-C₈-cycloalkyl, heterocycloalkyl or            heterocycloalkyl-C₁-C₄-alkyl which may optionally be mono-            or polysubstituted by identical or different radicals from            the group consisting of hydroxy, halogen, cyano,            C₁-C₆-alkyl, C₁-C₆-alkoxy, where alkyl and alkoxy may            optionally be mono- or polysubstituted by identical or            different radicals from the group consisting of halogen and            an oxo group,        -   or represents C₂-C₆-alkenyl or C₂-C₆-alkynyl,        -   or represents aryl, 5- to 10-membered heteroaryl,            aryl-C₁-C₄-alkyl or 5- or 6-membered heteroaryl-C₁-C₄-alkyl,            where        -   aryl and heteroaryl may optionally be mono- or            polysubstituted by identical or different radicals from the            group consisting of halogen, hydroxy, cyano, C(═O)OH,            C(═O)OR^(a), C₁-C₃-alkyl, C₃-C₈-cycloalkyl and C₁-C₃-alkoxy;            as defined and described in WO 2015/091426 and US            2016/0311833, the entirety of each of which is herein            incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ggg-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is phenylene or 5- to 6-membered heteroarylene containing        1-3 heteroatoms chosen from O, S, and N, wherein ring A is        optionally substituted with lower alkyl that is further        optionally substituted,    -   Ring B is phenylene, 5- to 6-membered heterocycloalkylene        containing 1-3 heteroatoms chosen from O, S, and N, or 5- to        6-membered heteroarylene containing 1-3 heteroatoms chosen from        O, S, and N, wherein ring B is optionally substituted with lower        alkyl that is further optionally substituted,    -   R³ is chosen from hydrogen, lower alkyl optionally substituted        with alkoxy, amino, N-(alkyl)amino, N,N-(dialkyl)amino, or        phenyl, heterocycloalkyl, and heteroaryl,    -   wherein phenyl, heterocycloalkyl, and heteroaryl are optionally        substituted with one or two groups independently chosen from        lower alkyl and wherein alkoxy is optionally substituted with        tri(alkyl)silyl,    -   R⁴ is chosen from heteroarylene and arylene, each of which is        optionally substituted, or R⁴ and R³ taken together with the        nitrogen to which they are bound, form an optionally substituted        3- to 7-membered heterocycloalkyl ring, or R⁴ is an alkylene        chain having 1-3 carbon atoms that is optionally substituted        with one or two groups independently chosen from lower alkyl and        cycloalkyl, each of which groups is optionally substituted with        hydroxyl or alkoxy, or R⁴ is absent,    -   R⁵ is chosen from C(O)NR⁵¹, NR⁵², and O or R⁵ is absent,        provided that if R⁴ is absent, then R⁵ is absent,    -   R⁶ is an alkylene or alkenylene chain having one or two double        bonds,    -   wherein the alkylene or alkenylene chain has 2 to 10 carbon        atoms,    -   wherein the alkylene or alkenylene chain is optionally        substituted with one or two groups independently chosen from        lower alkyl and cycloalkyl, each of which groups is optionally        substituted with hydroxyl or alkoxy, and    -   further wherein one or two of the carbon atoms in the alkylene        chain is optionally replaced by an O, S, SO, SO₂, or NR⁶¹, and    -   wherein two of the carbon atoms in the alkylene chain, are        optionally connected by a two or three carbon atom alkylene        chain to form a 5- to 7-membered ring.    -   R⁷ is chosen from NR⁷¹ and O or R⁷ is absent,    -   R⁵¹ is chosen from hydrogen and lower alkyl,    -   R⁵² is chosen from hydrogen, lower alkyl, and —C(O)OR⁸¹,    -   R⁶¹ is chosen from hydrogen, lower alkyl, and —C(O)OR⁸¹,    -   R⁷¹ is chosen from hydrogen, lower alkyl, and —C(O)OR⁸¹, and    -   R⁸¹ is lower alkyl;        as defined and described in WO 2014/143672 and US 2016/0002265,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-hhh-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein HET is a heteroaryl selected from pyrazolyl, indolyl,        pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl,        pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-d]pyrimidinyl,        2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, imidazo[4,5-b]pyridinyl,        and purinyl, wherein said heteroaryl is substituted with R_(a)        and R_(b);    -   R_(a) is H, F, Cl, Br, —CN, —OH, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,        C₁₋₄hydroxyalkyl, C₁₋₄ alkoxy, —NH₂, —NH(C₁₋₄ alkyl), —N(C₁₋₄        alkyl)₂, —NH(C₁₋₄ hydroxyalkyl), —NH(C₁₋₄ fluoroalkyl), —NH(C₁₋₆        hydroxy-fluoroalkyl), —C(O)NH₂, —CH₂NHC(O)(C₁₋₆ alkyl),        —CH₂NHC(O)(C₁₋₆ hydroxyalkyl), —CH₂NHC(O)NH(C₁₋₆ alkyl),        —CH₂NHC(O)NHCH₂(phenyl), —CH₂NHC(O)N(C₁₋₄ alkyl)₂,        —CH₂NHC(O)O(C₁₋₄ alkyl), —CH₂NHC(O)(C₃₋₆ cycloalkyl),        —CH₂NHC(O)(tetrahydrofuranyl), —CH₂NHC(O)CH₂(C₃₋₆ cycloalkyl),        —CH₂NHC(O)CH₂(tetrahydropyranyl), —CH₂NHC(O)CH₂(phenyl),        —NHC(O)(C₁₋₄ alkyl), pyrrolidinyl, hydroxypyrrolidinyl, or        pyridazinyl;    -   R_(b) is H or —NH₂;    -   R₁ is:        -   (i) C₁₋₆ alkyl, C₁₋₆ fluoro alkyl, C₁₋₆ hydroxyalkyl, C₁₋₈            hydroxy-fluoroalkyl, —(C₁₋₆ alkylenyl)O(C₁₋₄ alkyl), —(C₁₋₆            alkylenyl)O(C₁₋₄fluoroalkyl), —(C₁₋₆ fluoroalkylenyl)O(C₁₋₄            alkyl), —(C₁₋₆fluoroalkylenyl)O(C₁₋₄ deuteroalkyl), —(C₁₋₆            fluoroalkylenyl)O(C₁₋₄fluoroalkyl), —(C₁₋₄            fluoroalkylenyl)C(C₃₋₆ cycloalkyl)₂(OH),            —(C₁₋₄alkylenyl)NHC(O)(C₁₋₄ alkylenyl)OC(O)(C₁₋₃ alkyl),            —(C₁₋₆alkylenyl)NHS(O)₂(C₁₋₄ alkyl), —(C₁₋₆            alkylenyl)P(O)(C₁₋₄ alkoxy)₂, —(C₁₋₆ fluoroalkylenyl)NH(C₁₋₄            alkyl), —(C₁₋₆ alkylenyl)C(O)NH(C₁₋₄ alkyl), —(C₁₋₆            fluoroalkylenyl)C(O)NH(C₁₋₄ alkyl),            —(C₁₋₆fluoroalkylenyl)C(O)NH(C₁₋₄ hydroxyalkyl), or            -(C₆fluoroalkylenyl)OP(O)(OH)₂;        -   (ii) —(C₁₋₃ alkylenyl)R_(x), —(C₁₋₃ fluoroalkylenyl)R_(x),            —(C₁₋₃alkylenyl)C(O)R_(x), —(C₁₋₃ alkylenyl)C(O)NHR_(x),            —(C₁₋₃fluoroalkylenyl)C(O)R_(x), or            —CH₂CF=(tetrahydropyranyl), wherein R_(x) is a cyclic group            selected from C₃₋₆ cycloalkyl, tetrazolyl,            1,1-dioxidotetrahydrothiophenyl, 1,1-dioxidothiomorpholinyl,            oxadiazolyl, piperidinyl, piperazinyl, pyrrolidinyl,            oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyridinyl,            imidazolyl, morpholinyl, phenyl, and triazinyl, wherein each            cyclic group is substituted with zero to 3 substituents            independently selected from F, —OH, —CH₃, —C(CH₂)₂OH, —OCH₃,            —C(O)CH₂CN, —S(O)₂CH₃, —S(O)₂NH₂, —NHC(O)CH₃, —N(S(O)₂CH₃)₂,            —CH₂CH₂(acetamidophenyl), —CH₂CH₂(methoxyphenyl),            —CH₂CH₂(sulfamoylphenyl), oxetanyl, benzyl, and morpholinyl;        -   (iii) C₃₋₆ cycloalkyl or C₄₋₆ cycloalkenyl, each substituted            with zero to 3 substituents independently selected from F,            —OH, —CN, C₁₋₃alkyl, C₁₋₃ alkoxy, —S(C₁₋₃ alkyl), —NO₂,            —S(O)₂(C₁₋₃ alkyl), C₁₋₄hydroxyalkyl, —C(C₁₋₃            alkyl)(OH)(C₃₋₆ cycloalkyl), —CH₂C(O)NH(C₁₋₃ alkyl),            —NHC(O)(C₁₋₃ alkyl), —NHC(O)(C₁₋₄hydroxyalkyl), —C(O)NH(C₁₋₃            alkyl), —C(O)NH(C₁₋₃ deuteroalkyl), —C(O)NH(C₃₋₆            cycloalkyl), —NHC(O)O(C₁₋₃ alkyl), —NHS(O)₂(C₁₋₃alkyl),            pyridinyl, imidazolyl, pyrazolyl, methylimidazolyl,            methylpyrazolyl, and thiazolyl;        -   (iv) tetrahydropyranyl, piperidinyl, pyrazolyl, phenyl,            pyridinyl, or pyrimidinyl, each substituted with zero to 1            substituent selected from —OH, C₁₋₃ alkyl, C₁₋₃ fluoroalkyl,            C₁₋₄ hydroxyalkyl, C₁₋₃alkoxy, —C(O)(C₁₋₄ alkyl),            —S(O)₂(C₁₋₄ alkyl), —S(O)₂NH(C₁₋₄ alkyl), —NH(C₁₋₃ alkyl),            —N(C₁₋₃ alkyl)₂, —O(C₁₋₃ alkylenyl)N(C₁₋₃ alkyl)₂,            —CH₂(morpholinyl), azetidinyl, oxetanyl, tetrahydropyranyl,            morpholinyl, piperazinyl, piperidinyl, methylpiperazinyl,            methoxypiperidinyl, pyridinyl, pyrimidinyl, methylsulfonyl            azetidinyl, and —C(O)(methylsulfonyl azetidinyl); or        -   (v) pyrrolo[2,3-c]pyridinyl, bicyclo[2.2.1]heptan-1-ol,            tetrahydrobenzo[d]thiazol-2-amine, or            1,3-diazaspiro[4.5]decane-2,4-dione; and    -   R₂ is:        -   (i) C₁₋₇ alkyl or C₂₋₆ alkenyl, each substituted with zero            to three substituents independently selected from F, —OH,            and —CN; —(C₁₋₄ alkylenyl)O(C₁₋₄ alkyl), —(C₁₋₄            alkylenyl)O(C₁₋₄ fluoroalkyl), —(C₁₋₆ alkylenyl)NH₂, —(C₁₋₆            alkylenyl)S(O)₂(C₁₋₃ alkyl), —(C₁₋₆ fluoroalkylenyl)NH(C₁₋₃            alkyl), or —(C₁₋₆ alkylenyl)NHC(O)(C₁₋₄fluoroalkyl);        -   (ii) —(C₁₋₄ alkylenyl)R_(y) wherein R_(y) is C₃₋₆            cycloalkyl, azetidinyl, oxetanyl, oxazolyl, pyridinyl,            tetrahydropyranyl, or morpholinyl, each substituted with            zero to 2 substituents independently selected from F, —OH,            and C₁₋₃ alkyl;        -   (iii) C₃₋₆ cycloalkyl, azetidinyl, oxetanyl, furanyl,            tetrahydrofuranyl, pyrrolidinyl, piperidinyl, or            tetrahydropyranyl, each substituted with zero to 3            substituents independently selected from F, —OH, C₁₋₃alkyl,            C₁₋₃ hydroxyalkyl, —C(O)(C₁₋₃ alkyl), —C(O)(C₁₋₃            fluoroalkyl), —C(O)(C₁₋₃ cyanoalkyl), —C(O)O(C₁₋₃ alkyl),            —C(O)NH₂, —C(O)NH(C₁₋₃ alkyl), —C(O)(difluorophenyl), —NH₂,            —NH(C₁₋₃ alkyl), —NH(C₁₋₃ fluoroalkyl), —NH(oxetanyl),            —NHC(O)(C₁₋₃ alkyl), —NHC(O)(C₁₋₃ fluoroalkyl), —NHC(O)(C₃₋₆            cycloalkyl), —NHC(O)(fluorophenyl), —S(O)₂(C₁₋₃ alkyl),            imidazolyl, phenyl, pyrimidinyl, fluoropyrimidinyl,            chloropyrimidinyl, and methoxypyrimidinyl;        -   (iv) adamantanyl, hydroxyadamantanyl, benzo[d]imidazolyl,            benzo[d]oxazolyl, benzo[d]triazolyl, benzothiazolyl,            bicyclo[1.1.1]pentanyl, or hydroxy-bicyclo[2.2.1]heptanyl;            or        -   (v) phenyl, pyrazolyl, thiazolyl, thiadiazolyl, or            indazolyl, each substituted with 0 to 2 substituents            independently selected from F, Cl, —OH, —CN, C₁₋₄ alkyl,            C₁₋₄ hydroxyalkyl, C₁₋₄ fluoroalkyl, C₁₋₄cyanoalkyl, C₁₋₃            alkoxy, C₃₋₆ cycloalkyl, —(C₁₋₃ alkylenyl)O(C₁₋₃ alkyl),            —(C₁₋₃ alkylenyl)O(C₁₋₃ fluoroalkyl), —C(O)NH₂, —C(O)NH(C₁₋₃            alkyl), —NHC(O)(C₁₋₃ alkyl), —NHC(O)S(O)₂(C₁₋₃alkyl),            —S(O)₂NH₂, —S(O)₂(C₁₋₃ alkyl), pyrazolyl, methyl pyrazolyl,            imidazolyl, triazolyl, methyl tetrazolyl, ethyl tetrazolyl,            phenyl, pyrimidinyl, fluoropyrimidinyl, and            tetrahydropyranyl;            as defined and described in WO 2015/103453 and US            2015/0191464, the entirety of each of which is herein            incorporated by reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-iii-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein        is a single or double bond;    -   W is selected from CH, CH—CH, O, S, NR⁶, and CO;    -   Y is N or CR⁹;    -   Z is N or C, and Z is N if W is CH and Y is CR⁹;    -   R⁴ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R⁸, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted carbocycle, an optionally substituted        C₁-C₆, alkyl, an optionally substituted C₁-C₆ haloalkyl, an        optionally substituted C₁-C₆heteroalkyl, an optionally        substituted C₁-C₆ alkenyl, an optionally substituted C₁-C₆        alkynyl, CO₂R⁶, SO₃R⁶, SO₂R⁶ and SO₂NR⁷R⁸;    -   R⁵ is selected from hydrogen, halogen, OR⁶, an optionally        substituted C₁-C₆ alkyl, an optionally substituted C₁-C₆        haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆haloheteroalkyl, an optionally        substituted C₁-C₆ alkenyl, and an optionally substituted C₁-C₆        alkynyl;    -   or R⁴ and R⁵ are linked to form an optionally substituted        non-aromatic ring;    -   each R⁶ is independently selected from an optionally substituted        aryl, an optionally substituted heteroaryl, and an optionally        substituted non-aromatic ring, each optionally fused with a        substituted aryl or a substituted heteroaryl, hydrogen, an        optionally substituted C₁-C₁₀alkyl, an optionally substituted        C₁-C₁₀ haloalkyl, and an optionally substituted C₁-C₁₀        heteroalkyl;    -   each R⁷ and R⁸ is independently selected from an optionally        substituted aryl, an optionally substituted heteroaryl, an        optionally substituted non-aromatic ring, each optionally fused        with a substituted aryl or a substituted heteroaryl, hydrogen,        an optionally substituted C₁-C₁₀ alkyl, an optionally        substituted C₁-C₁₀ haloalkyl, an optionally substituted C₁-C₁₀        alkenyl, an optionally substituted C₁-C₁₀ alkynyl, and an        optionally substituted C₁-C₁₀heteroalkyl, or R⁷ and R⁸ are        linked to form an optionally substituted non-aromatic ring;    -   R⁹ is selected from hydrogen, halogen, OR⁶, CN, NR⁷R′, CH₂OR⁶,        an optionally substituted aryl, an optionally substituted        heteroaryl, an optionally substituted non-aromatic ring, an        optionally substituted C₁-C₆ alkyl, an optionally substituted        C₁-C₆ haloalkyl, an optionally substituted C₁-C₆ heteroalkyl, an        optionally substituted C₁-C₆ alkenyl, an optionally substituted        C₁-C₆ alkynyl, CO₂R⁶, SO₃R⁶, and SO₂NR⁷R⁸;    -   A is an optionally substituted aryl or an optionally substituted        heteroaryl group;    -   each optionally substituted group is either unsubstituted or        substituted with one or more groups independently selected from        alkyl, heteroalkyl, alkenyl, alkynyl, haloalkyl,        heterohaloalkyl, aryl, arylalkyl, heteroaryl, non-aromatic ring,        hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano,        halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl,        O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido,        N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato,        isothiocyanato, nitro, silyl, trihalomethanesulfonyl, ═O, ═S,        amino, and protected derivatives of amino groups;        as defined and described in WO 2012/068546 and US 2014/0155379,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-jjj-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Q denotes Ar or Het;    -   E denotes —(CH₂)_(m)CO—, —(CH₂)_(m)SO₂, —(CH₂)_(q)-,        —(CH₂)_(m)NHCO—, or a single bond;    -   R¹ denotes H, OH, NH—C₁-C₆-alkyl, OC₁-C₆-alkyl, C₁-C₆-alkyl,        C₂-C₆-alkenyl, C₂-C₆-alkynyl, Cyc, Hal, Het¹, O-Het¹, CO-Het¹,        NH-Het¹, CO—Ar¹, O—Ar¹, Ar¹, NH—Ar¹, —(CH₂)_(q)Het¹,        —CONH—(CH₂)_(q)Het¹, —CONH-Het¹, —(CH₂)_(q)O-Het¹,        —(CH₂)_(q)O—Ar¹, —(CH₂)_(q)Ar¹, —CONH—(CH₂)_(q)Ar¹, —CONH—Ar¹,        —CONHC₃-C₆-cycloalkyl, —(CH₂)_(q)Hal, —(CH₂)_(q)Cyc, CF₃,        —(CH₂)_(s)NH—(CH₂)_(q)-Het, —(CH₂)_(s)NH—(CH₂)_(q)—Ar¹, wherein        NH—C₁-C₆-alkyl, OC₁-C₆-alkyl, C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₆-cycloalkyl may be substituted by 1 to 3        groups independently selected from OC₁-C₃-alkyl, OH, CONH₂, NH₂;    -   R² denotes H, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, Hal,        CF₃, preferably H;    -   R³ denotes Het¹, Ar¹, NR^(a)R^(b), COOH, —(CH₂)_(q)Het¹,        —(CH₂)_(q)Ar¹, —(CH₂)_(q)NR^(a)R^(b), —(CH₂)_(q)COOH, or        C₁-C₆-alkyl wherein 1 to 3 hydrogen atoms may be independently        replaced by OH or CF₃;    -   R⁴ denotes H, C₁-C₆-alkyl, C₂-C₆-alkenyl, Hal;    -   R^(a) denotes H, linear, branched or cyclic C₁-C₆-alkyl;    -   R^(b) denotes H, Het^(b), Ar^(b), —CO-Het^(b), —CO—Ar^(b), a        C₃-C₈-cycloalkyl or a linear or branched alkyl having 1 to 6        carbon atoms, wherein 1 to 3 hydrogen atoms may be replaced by        Het^(b), Ar^(b), NH₂, N(C₁-C₆-alkyl)₂, NH(C₁-C₆-alkyl),        N(C₁-C₆-alkyl)(C₃-C₈-cycloalkyl), NH(C₃-C₈-cycloalkyl),        O(C₁-C₆-alkyl), CN, OH, CF₃, Hal;    -   n is 0, 1, 2, 3 or 4;    -   m is 0, 1, 2, 3 or 4;    -   q is 1, 2, or 3;    -   s is 0, 1, 2 or 3;    -   Hal denotes Cl, Br, I, F, preferably Cl or F;    -   Ar denotes a divalent monocyclic or fused bicyclic arylen group        having 6 to 14 carbon atoms, which may be further substituted        with 1 to 4 substitutents selected from Hal, C₁-C₆-alkyl,        —(CH₂)_(m)OC₁-C₆-alkyl, CN, OH, NO₂, CF₃, —(CH₂)_(m)COOH,        —(CH₂)_(m)COOC₁-C₆-alkyl;    -   Het denotes a divalent monocyclic or fused bicyclic unsaturated,        saturated or aromatic heterocyclic group having 1 to 5        heteroatom independently selected from N, O, S and/or a group        —C═O, which may be further substituted with 1 to 4 substituent        selected from Hal, C₁-C₆-alkyl, —(CH₂)_(m)OC₁-C₆-alkyl, CN, OH,        NO₂, CF₃, —(CH₂)_(m)COOH, —(CH₂)_(m)COOC₁-C₆-alkyl;    -   Ar¹ denotes a monocyclic or bicyclic, aromatic carbocyclic ring        having 6 to 14 carbon atoms, which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by Hal, —CF₃,        —OCF₃, —NO₂, —CN, perfluoroalkyl, Hal, —CF₃, —OCF₃, —NO₂, —CN,        perfluoroalkyl, linear or branched C₁-C₆-alkyl, cycloalkyl, —OH,        —OC₁-C₆-alkyl, —COC₁-C₆-alkyl, —NH₂, —COH, —COOH, —CONH₂, a        group R^(b) such as —CH₂O(C₁-C₆-alkyl), —SO₂NR^(a)R^(b) or        SO₂(C₁-C₆alkyl);    -   Het¹ denotes a monocyclic or bicyclic (fused, bridged or spiro)        saturated, unsaturated or aromatic heterocyclic ring having 1 to        4 heteroatom independently selected from N, O, S and/or a CO        group, which is unsubstituted or monosubstituted, disubstituted        or trisubstituted by Hal, —CF₃, —OCF₃, —NO₂, —CN,        perfluoroalkyl, linear or branched C₁-C₆-alkyl,        C₃-C₈-cycloalkyl, —OH, —OC₁-C₆-alkyl, —NH₂, —N(C₁-C₆-alkyl)₂,        —COH, —COOH, —CONH₂, —COC₁-C₆-alkyl, —NHCO(C₃-C₆cycloalkyl), a        group R^(b)—SO₂NR^(a)R^(b) or SO₂(C₁-C₆alkyl);    -   Het^(b) denotes a monocyclic or bicyclic (fused or spiro)        saturated, unsaturated or aromatic heterocyclic ring having 1 to        4 heteroatom independently selected from N, O, S and/or a CO        group, which is unsubstituted or monosubstituted, disubstituted        or trisubstituted by Hal, —CF₃, —OCF₃, —NO₂, —CN,        perfluoroalkyl, —OH, —OC₁-C₆-alkyl, —NH₂, —COH, —COOH, —CONH₂,        or by a linear or branched C₁-C₆-alkyl wherein 1 to 3 hydrogen        atoms may be replaced by NH₂, N(C₁-C₆-alkyl)₂, NH(C₁-C₆-alkyl),        N(C₁-C₆-alkyl)(C₃-C₈-cycloalkyl), NH(C₃-C₈-cycloalkyl),        O(C₁-C₆-alkyl), CN, OH, CF₃, Hal, C₃-C₈-cycloalkyl, or by a 4 to        8-membered heterocyclic ring containing an heteroatom selected        from O, S and N;    -   Ar^(b) denotes a monocyclic or bicyclic, aromatic carbocyclic        ring having 6 to 14 carbon atoms, which is unsubstituted or        monosubstituted, disubstituted or trisubstituted by Hal, —CF₃,        —OCF₃, —NO₂, —CN, perfluoroalkyl, Hal, —CF₃, —OCF₃, —NO₂, —CN,        perfluoroalkyl, —OH, —OC₁-C₆-alkyl, —NH₂, —COH, —COOH, —CONH₂,        or by a linear or branched C₁-C₆-alkyl wherein 1 to 3 hydrogen        atoms may be replaced by NH₂, N(C₁-C₆-alkyl)₂, NH(C₁-C₆-alkyl),        N(C₁-C₆-alkyl)(C₃-C₈-cycloalkyl), NH(C₃-C₈-cycloalkyl),        O(C₁-C₆-alkyl), CN, OH, CF₃, Hal, C₃-C₈-cycloalkyl, or by a 4 to        8-membered heterocyclic ring containing an heteroatom selected        from O, S and N;    -   Cyc denotes a saturated or unsaturated carbocyclic ring having 3        to 8 carbon atoms, preferrably 5 or 6 carbon atoms, wherein 1 to        5 H atoms are replaced by Hal, —CF₃, —OCF₃, —NO₂, —CN,        perfluoroalkyl, Hal, —CF₃, —OCF₃, —NO₂, —CN, perfluoroalkyl,        linear or branched C₁-C₆-alkyl, cycloalkyl, —OH, —OC₁-C₆-alkyl,        —COC₁-C₆-alkyl, —NH₂, —COH, —COOH, —CONH₂, a group R such as        —CH₂O(C₁-C₆-alkyl), —SO₂NR^(a)R^(b) or SO₂(C₁-C₆alkyl); or        as defined and described in WO 2012/084704 and US 2013/0274241,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-kkk-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   R¹ is aryl, heteroaryl, heterocyclyl or (C₁₋₆ alkyl)R⁶, wherein        said aryl, heteroaryl, and heterocyclyl groups are optionally        substituted with one or two substituents selected from the group        consisting of halo, cyano, R⁴, C₃₋₈ cycloalkyl, C₁₋₃ aminoalkyl,        C₁₋₃hydroxyalkyl, OR⁴, NR⁴R⁵, NR⁴COR⁶, NR⁴SO₂R⁶, SO₂NR⁴R⁵,        CONR⁴R⁵ and CONR⁴R⁵;    -   R² is aryl, heteroaryl, C₃₋₈ cycloalkyl, heterocyclyl or (C₁₋₆        alkyl)R⁶, wherein said aryl, heteroaryl, cycloalkyl and        heterocyclyl groups are optionally substituted with one or two        substituents selected from the group consisting of halo, cyano,        oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴, O(C₃₋₈ cycloalkyl),        (C═O)OR⁴, SO_(m)R⁶, SO_(m)R⁴, NR⁴R⁵, SO₂NR⁴R⁵ and NR⁴SO₂R⁶;    -   R³ is halo, cyano, oxo, hydroxyl, imino, hydroxyimino, R⁴, OR⁴,        C₃₋₈cycloalkyl, SO_(m)R⁶, SO_(m)R⁴NR⁴R⁵ or (C═O)NR⁴R⁵,        NR⁴(CO)R⁶, SO_(m)NR⁴R⁵ and NR⁴SO₂R⁶;    -   R⁴ is hydrogen or C₁₋₆ alkyl, wherein said alkyl is optionally        substituted with one to three halo or hydroxyl;    -   R⁵ is hydrogen or C₁₋₆ alkyl, wherein said alkyl is optionally        substituted with halo or hydroxyl;    -   R⁶ is aryl, heteroaryl, C₃₋₈ cycloalkyl or heterocyclyl;    -   m is an integer from zero to two;        as defined and described in WO 2012/129258 and US 2014/0194404,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein

IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-lll-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is —N═ or —CH═;    -   Y is selected from the group consisting of —NR²—, —CH₂—, —CHR—        and —O—, such that when Y is —CHR—, R and R³ together with the        carbon to which they are attached optionally form a 4- to        6-membered cycloalkyl, cycloalkenyl or heterocyclic ring,        wherein the 4- to 6-membered cycloalkyl, cycloalkenyl, or        heterocyclic ring is optionally substituted with one to three        substituents independently selected from the group consisting of        C₁₋₄ alkyl, C₃₋₆ cycloalkyl, phenyl, CF₃, heterocyclyl, halogen,        —COOR⁸, —NHR⁸, —SR⁸, —OR⁸, —SO₂R⁸, —COR⁸, —NHCOR⁸, and —CONHR⁸;        or when Y is —NR²—, R² and R³ together with the nitrogen to        which they are attached optionally form a 4- to 6-membered        heterocyclic ring, wherein the 4- to 6-membered heterocyclic        ring is optionally substituted with one to three substituents        independently selected from the group consisting of C₁₋₄ alkyl,        C₃₋₆ cycloalkyl, phenyl, CF₃, heterocyclyl, halogen, —COOR⁸,        —NHR⁸, —SR⁸, —OR⁸, —SO₂R⁸, —COR⁸, —NHCOR⁸, and —CONHR⁸;    -   R¹ is selected from the group consisting of hydrogen, C₁₋₁₀        alkyl, C₃₋₈cycloalkyl, aryl, heterocyclyl, halogen, —COOR⁷,        —NHR⁷, —SR⁷, —OR⁷, —SO₂R⁷, —COR⁷, —NHCOR⁷, and —CONHR⁷; wherein        said alkyl, cycloalkyl, aryl and heterocyclyl are optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₄ alkyl, C₃₋₆        cycloalkyl, CN, phenyl, CF₃, heterocyclyl, halogen, —COOR⁸,        —NHR⁸, —SR⁸, —OR⁸, —SO₂R⁸, —COR⁸, —NHCOR⁸, and —CONHR⁸, wherein        said —NHR⁸ is optionally substituted with —N(C₁₋₄alkyl)NH₂ or        —N(C₃₋₆ cycloalkyl)NH₂;    -   R² is selected from the group consisting of hydrogen, C₁₋₁₀        alkyl, and C₃₋₈ cycloalkyl;    -   R³ is selected from the group consisting of hydrogen, C₁₋₁₀        alkyl, C₃₋₈cycloalkyl, aryl, heterocyclyl, and —COOR⁷; wherein        said alkyl, cycloalkyl, aryl and heterocyclyl are optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₄ alkyl, C₃₋₆        cycloalkyl, phenyl, CF₃, heterocyclyl, halogen, —COOR⁸, —NHR⁸,        —SR⁸, —OR⁸, —SO₂R⁸, —COR⁸, —NHCOR⁸, and —CONHR⁸;    -   R⁶ is selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₈        cycloalkyl, aryl, heterocyclyl, —COOR⁷, —SO₂R⁷, and —COR⁷;        wherein said alkyl, cycloalkyl, aryl and heterocyclyl are        optionally substituted with one to three substituents        independently selected from the group consisting of C₁₋₄ alkyl,        C₃₋₆ cycloalkyl, phenyl, CF₃, heterocyclyl, halogen, —COOR⁸,        —NHR⁸, —SR⁸, —OR⁸, —SO₂R⁸, —COR⁸, —NHCOR⁸, and —CONHR⁸;    -   R⁷ is selected from the group consisting of hydrogen, C₁₋₁₀        alkyl, C₃₋₈ cycloalkyl, aryl, and heteroaryl; wherein said        alkyl, cycloalkyl, aryl and heterocyclyl are optionally        substituted with one to three substituents independently        selected from the group consisting of C₁₋₄ alkyl,        C₃₋₆cycloalkyl, phenyl, CF₃, heterocyclyl, halogen, —COOR⁸,        —NHR⁸, —SR⁸, —OR⁸, —SO₂R⁸, —COR⁸, —NHCOR⁸, and —CONHR⁸; and    -   R⁸ is selected from the group consisting of hydrogen, C₁₋₆ alkyl        and C₃₋₆ cycloalkyl;        as defined and described in WO 2013/066729 and US 2014/0329799,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-mmm-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is independently CH or N;    -   Y is H or methyl;    -   a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4;    -   Ring A is (C₃-C₈)cycloalkenyl, aryl or heterocycle optionally        substituted with one to three substituents independently        selected from R₁;    -   R₁ is selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,        (C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H, halo, OH,        O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)NR₅R₆, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R₂ and R₃ are independently selected from: H,        (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, (C═O)_(a)O_(b) heterocyclyl, CO₂H, CN,        O_(b)C₁-C₆fluoroalkyl, O_(a)(C═O)_(b)NR₅R₆, CHO, (N═O)R₅R₆,        S(O)_(m)NR₅R₆, SH, S(O)_(m)—(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)C₃-C₈        cycloalkyl, optionally substituted with one or more substituents        selected from R₁; or R₂ and R₃ can be taken together with the        nitrogen to which they are attached to form a monocyclic or        bicyclic heterocycle with 3-7 members in each ring and        optionally containing, in addition to the nitrogen, one or two        additional heteroatoms selected from N, O and S, said monocyclic        or bicyclic heterocycle optionally substituted with one or more        substituents selected from R₁;    -   R₄ is independently selected from: (C₁-C₆)alkyl, OH, methoxy,        CF₃ and F, said alkyl optionally substituted with OH;    -   R₅ and R₆ are independently selected from H,        (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl,        CO₂H, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)N(R_(a))₂, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R_(a) is independently selected from R_(b), OH, (C₁-C₆)alkoxy,        halogen, cyclopropyl, CO₂H, CN, O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo,        and N(R_(b))₂; and    -   R_(b) is independently selected from H and (C₁-C₆)alkyl;        as defined and described in WO 2014/058685 and US 2015/0299224,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-nnn-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is CH or N;    -   a is 0 or 1; b is 0 or 1; m is 0, 1 or 2;    -   Ring A is (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkenyl, aryl or        heterocycle optionally substituted with one to three        substituents independently selected from R₁;    -   R₁ is selected from: H, oxo, (C═O)_(a)O_(b)(C₁-C₁₀)alkyl,        (C═O)_(a)O_(b)-aryl, (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl, CO₂H, halo, OH,        O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)NR₅R₆, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m)NR₅R₆, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R₂ and R₃ are independently selected from: H,        (C═O)_(a)O_(b)C₁-C₁₀ alkyl, (C═O)_(a)O_(b)aryl, C₂-C₁₀ alkenyl,        C₂-C₁₀ alkynyl, (C═O)_(a)O_(b) heterocyclyl, CO₂H, CN,        O_(b)C₁-C₆ fluoroalkyl, O_(a)(C═O)_(b)NR₅R₆, CHO, (N═O)R₅R₆,        S(O)_(m)NR₅R₆, SH, S(O)_(m)—(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)C₃-C₅        cycloalkyl, optionally substituted with one or more substituents        selected from R₁; or R₂ and R₃ can be taken together with the        nitrogen to which they are attached to form a monocyclic or        bicyclic heterocycle with 3-7 members in each ring and        optionally containing, in addition to the nitrogen, one or two        additional heteroatoms selected from N, O and S, said monocyclic        or bicyclic heterocycle optionally substituted with one or more        substituents selected from R₁;    -   R₄ is selected from: (C₁-C₆)alkyl and (C₃-C₆)cycloalkyl,        optionally substituted with R_(a);    -   R₅ and R₆ are independently selected from: H, oxo,        (C═O)_(a)O_(b)(C₁-C₁₀)alkyl, (C═O)_(a)O_(b)-aryl,        (C═O)_(a)O_(b)(C₂-C₁₀)alkenyl, (C═O)_(a)O_(b)(C₂-C₁₀)alkynyl,        CO₂H, O_(b)(C₁-C₆)fluoroalkyl, (C═O)_(a)N(R_(a))₂, CN,        (C═O)_(a)O_(b)(C₃-C₈)cycloalkyl, S(O)_(m) N(R_(a))₂, SH,        S(O)_(m)—(C₁-C₁₀)alkyl and (C═O)_(a)O_(b)-heterocyclyl, said        alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are        optionally substituted with one or more substituents selected        from R_(a);    -   R_(a) is independently selected from R_(b), OH, (C₁-C₆)alkoxy,        halogen, cyclopropyl, CO₂H, CN, O_(a)(C═O)_(b)(C₁-C₆)alkyl, oxo,        and N(R_(b))₂; and    -   R_(b) is independently selected from H and (C₁-C₆)alkyl;        as defined and described in WO 2014/058691 and US 2015/0274708,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-nnn′-1

or a pharmaceutically acceptable salt thereof, wherein L and LBM are asdefined above and described in embodiments herein, and wherein each ofthe variables R₃, R₄, X, and Ring A is as defined and described in WO2014/058691, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ooo-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Z denotes a group

wherein

-   -   X is CH or N;    -   Y is CH or N;    -   Ra, Rc, R1 denote each independently H, Hal or A1;    -   Rb is H or alkyl;    -   A1 is branched or linear alkyl having 1 to 12 C-atoms, wherein        one or more, such as 1 to 7, H atoms may be replaced by Hal,        OR^(b), COOR^(b), CN or N(Rb)₂ and wherein one or more,        preferably 1 to 5 CH₂-groups may be replaced by O, CO, NRb or S,        SO, SO₂, 1,2-, 1,3- or 1,4-phenylen, —CH═CH— or —C═C—; and    -   Hal denotes F, Cl, Br, I;        as defined and described in WO 2014/121931 and US 2015/0376167,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-ppp-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   R1, R3 denote each, independently of one another H,        (CH₂)_(p)CON(R5)₂, OA, Hal, COOH, COOA, (CH₂)_(p)NHCOA,        (CH₂)_(p)Het1, (CH₂)_(p)NR2R5, or OH;    -   R2 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms,        wherein one or two H atoms of the alkyl group are optionally        replaced by OR6, NR5R6, NHCOR5, CONR5R6;    -   R4 denotes H or A;    -   R5 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms;    -   R6 denotes H or linear or branched alkyl with 1, 2 or 3 C atoms;    -   Z is absent or denotes Ar-diyl or Het-diyl;    -   L denotes (CH₂)_(n) wherein one or two CH₂groups are optionally        replaced by 0 and/or a CH═CH-group, and/or wherein one or two H        atoms are optionally replaced by OR2, NR2R5 or Het1;    -   Ar-diyl denotes 1,2-, 1,3- or 1,4-phenylen optionally        substituted with from 1 to 5 groups independently selected from        the group consisting of Hal, CN, —CF₃, —OCF₃, OH, O-A, SO₂-A,        COOH, COOA, —CO-A, O-phenyl, SO₂-phenyl, SO₂—CF₃, Het2 and A;    -   Het-diyl denotes an unsaturated, saturated or aromatic 5- or        6-membered heterocycle comprising 1 to 2 N, O and/or S atoms,        which are optionally unsubstituted or mono-, di- or        trisubstituted by Hal, CN, —CF₃, —OCF₃, O-A, SO₂-A, COOH, COOA,        —CO-A, O-phenyl, SO₂-phenyl, SO₂—CF₃, Het2 and/or A;    -   A denotes an unbranched or branched alkyl comprising 1 to 10 C        atoms, in which 1 to 5 H atoms are optionally replaced by F        and/or in which one or two non-adjacent CH₂ groups are        optionally replaced by O;    -   Het1 denotes morpholinyl, piperidinyl or pyrrolidinyl;    -   Het2 denotes morpholinyl, piperidinyl or pyrrolidinyl;    -   Hal denotes F, Cl, Br, I;    -   n denotes 1, 2, 3, 4, 5 or 6;    -   p denotes 0, 1 or 2;        as defined and described in WO 2014/121942 and US 2015/0376206,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and/or IRAK4 inhibitor

thereby forming a compound of formula I-qqq-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein Ring A is a 3-7 membered saturated or partially        unsaturated carbocyclic ring or a 4-7 membered saturated or        partially unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   n is 0-4;    -   each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR,        —SR, —N(R)₂, —SO₂R, —SO₂N(R)₂, —SOR, —C(O)R, —CO₁R, —C(O)N(R)₂,        —C(O)N(R)—OR, —NRC(O)R, —NRC(O)N(R)₂, Cy, or —NRSO₂R; or R¹ is        selected from one of the following formulas:

-   -   or two R¹ groups are taken together with their intervening atoms        to form an optionally substituted 4-7 membered fused,        spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each Cy is an optionally substituted ring selected from a 3-7        membered saturated or partially unsaturated carbocyclic ring or        a 4-7 membered saturated or partially unsaturated heterocyclic        ring having 1-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;    -   each R is independently hydrogen or an optionally substituted        group selected from C₁₋₆ aliphatic, aryl, 4-7 membered saturated        or partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, or sulfur;    -   R^(z) is —R, —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R,        —N(R)₂, —OR, or —SO²N(R)₂;    -   Ring B is an unsubstituted 4-8 membered partially unsaturated        carbocyclic fused ring; and    -   L is a C₁₋₆ bivalent hydrocarbon chain wherein one or two        methylene units of the chain are optionally and independently        replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, —SO₂N(R)—,        —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;        as defined and described in WO 2012/097013 and US 2012/0283238,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and/or IRAK4 inhibitor

thereby forming a compound of formula I-rrr-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-7 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   n is 0-4;    -   each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR,        —SR, —N(R)₂, —SO₂R, —SO₂N(R)₂, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂,        —C(O)N(R)—OR, —NRC(O)OR, —NRC(O)N(R)₂, Cy, or —NRSO₂R; or R¹ is        selected from one of the following formulas:

-   -   or two R¹ groups are taken together with their intervening atoms        to form an optionally substituted 4-7 membered fused,        spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each Cy is an optionally substituted ring selected from a 3-7        membered saturated or partially unsaturated carbocyclic ring or        a 4-7 membered saturated or partially unsaturated heterocyclic        ring having 1-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, or sulfur;    -   Ring B is a cyclopento or cyclohexo fused ring;    -   m is 1-2;    -   p is 0-2;    -   W is N;    -   R^(z) is R, CN, NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R,        —N(R)C(O)OR, —NRC(O)N(R)₂, —OR, or —SO₂N(R)₂;    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —NR—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)SO₂—, —SO₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —SO—        or —SO₂—;    -   each L² is independently a covalent bond or a C₁₋₆ bivalent        hydrocarbon chain wherein one or two methylene units of the        chain are optionally and independently replaced by —NR—,        —N(R)C(O)—, —C(O)N(R)—, —N(R)SO₂—, —SO₂N(R)—, —O—, —C(O)—,        —OC(O)—, —C(O)O—, —S—, —SO— or —SO₂—;    -   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,        —SO₂R, —SO₂N(R)₂, —SOR, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R,        —NRC(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)S(O)₂N(R)₂,        —NRSO₂R, or an optionally substituted group selected from        C₁₋₆aliphatic, phenyl, 4-7 membered saturated or partially        unsaturated heterocyclic having 1-2 heteroatoms independently        selected from nitrogen, oxygen, or sulfur, or 5-6 membered        heteroaryl ring having 1-4 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, or:    -   two -L²(R⁴)_(p)—R⁴ groups are taken together with their        intervening atoms to form an optionally substituted 4-7 membered        fused, spiro-fused, or bridged bicyclic ring having 0-2        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;        as defined and described in WO 2013/106535 and US 2013/0231328,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and/or IRAK4 inhibitor

thereby forming a compound of formula I-sss-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein Ring A is a 3-7 membered saturated or partially        unsaturated carbocyclic ring or a 4-7 membered saturated or        partially unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   n is 0-4;    -   each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR,        —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —SOR, —C(O)R, —CO₂R,        —C(O)N(R)₂, —C(O)N(R)—OR, —N(R)C(O)R, —N(R)C(O)OR,        —N(R)C(O)N(R)₂, Cy, or —N(R)S(O)₂R, or R¹ is selected from one        of the following formulas:

-   -   or two R¹ groups are taken together with their intervening atoms        to form an optionally substituted 4-7 membered fused,        spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   each Cy is an optionally substituted ring selected from a 3-7        membered saturated or partially unsaturated carbocyclic ring or        a 4-7 membered saturated or partially unsaturated heterocyclic        ring having 1-3 heteroatoms independently selected from        nitrogen, oxygen, and sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;    -   Ring B is selected from a benzo fused ring and a 5-6 membered        heteroaromatic fused ring having 1-3 heteroatoms independently        selected from nitrogen, oxygen, and sulfur; wherein said Ring B        may be optionally substituted by one or more oxo, thiono, or        imino groups;    -   m is 0-4;    -   p is 0-2;    -   W is N or —C(R³)—;    -   R^(z) is R, CN, NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R,        —N(R)₂, —N(R)C(O)OR, —N(R)C(O)N(R)₂, —OR, or —S(O)₂N(R)₂;    -   R³ is hydrogen, halogen, —CN, C₁₋₄ aliphatic, C₁₋₄        haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂;    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   each L² is independently a covalent bond or a C₁₋₆ bivalent        hydrocarbon chain wherein one or two methylene units of the        chain are optionally and independently replaced by —N(R)—,        —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—,        —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; and    -   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,        —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —CO₂R, —C(O)N(R)₂,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,        —N(R)S(O)₂N(R)₂, —N(R)S(O)₂R, or an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur, or    -   two -L²(R)_(p)—R⁴ groups are taken together with their        intervening atoms to form an optionally substituted 4-7 membered        fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;        as defined and described in WO 2014/011902 and US 2014/0018343,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an RmAK1 and/or IRAK4 inhibitor

thereby forming a compound of formula I-ttt-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein Ring A is a 3-7 membered saturated or partially        unsaturated carbocyclic ring or a 4-7 membered saturated or        partially unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   n is 0-4;    -   each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR,        —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)N(R)₂, —C(O)N(R)—OR, —N(R)C(O)R, —N(R)C(O)OR,        —N(R)C(O)N(R)₂, Cy, or —N(R)S(O)₂R; or R¹ is selected from one        of the following formulas:

-   -   two R¹ groups are taken together with their intervening atoms to        form an optionally substituted 4-7 membered fused, spiro-fused,        or bridged bicyclic ring having 0-2 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;    -   each Cy is an optionally substituted ring selected from a 3-7        membered saturated or partially unsaturated carbocyclic ring or        a 4-7 membered saturated or partially unsaturated heterocyclic        ring having 1-3 heteroatoms independently selected from        nitrogen, oxygen, and sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;    -   Ring B is selected from a 4-8 membered partially unsaturated        carbocyclic fused ring and a 4-7 membered partially unsaturated        heterocyclic fused ring having 1-2 heteroatoms selected from        nitrogen, oxygen, and sulfur; wherein said Ring B may be        optionally substituted by one or more oxo, thiono, or imino        groups;    -   m is 0-4;    -   p is 0-2;    -   R^(z) is —R, —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R,        —N(R)₂, —N(R)C(O)OR, —N(R)C(O)N(R)₂, —OR, or —S(O)₂N(R)₂;    -   R³ is hydrogen, halogen, —CN, C₁₋₄ aliphatic, C₁₋₄        haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂;    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   each L² is independently a covalent bond or a C₁₋₆ bivalent        hydrocarbon chain wherein one or two methylene units of the        chain are optionally and independently replaced by —N(R)—,        —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—,        —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; and    -   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,        —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,        —N(R)S(O)₂N(R)₂, —N(R)S(O)₂R, or an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur, or    -   two -L²(R⁴)_(p)—R⁴ groups are taken together with their        intervening atoms to form an optionally substituted 4-7 membered        fused, spiro-fused, or bridged bicyclic ring having 0-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;        as defined and described in WO 2014/011906 and US 2014/0018357,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and/or IRAK4 inhibitor

thereby forming a compound of formula I-uuu-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Ring A is a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-7 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   n is 0-4;    -   each R¹ is independently —R, halogen, —CN, —NO₂, —OR, —CH₂OR,        —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)N(R)₂, —C(O)N(R)—OR, —N(R)C(O)R, —N(R)C(O)OR,        —N(R)C(O)N(R)₂, Cy, or —N(R)S(O)₂R; or R¹ is selected from one        of the following formulas:

-   -   or two R¹ groups are taken together with their intervening atoms        to form an optionally substituted 4-7 membered fused,        spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   each Cy is an optionally substituted ring selected from a 3-7        membered saturated or partially unsaturated carbocyclic ring or        a 4-7 membered saturated or partially unsaturated heterocyclic        ring having 1-3 heteroatoms independently selected from        nitrogen, oxygen, and sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, and sulfur;    -   each of R^(x) and R^(y) is independently —R, halogen, —CN, —NO₂,        —OR, —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)N(R)₂, —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R, or:    -   R^(x) and R^(y) are taken together with their intervening atoms        to form Ring B substituted with m occurrences of

-   -   Ring B is selected from a benzo fused ring, a 4-8 membered        partially unsaturated carbocyclic fused ring, a 4-8 membered        partially unsaturated heterocyclic fused ring having one or two        heteroatoms independently selected from nitrogen oxygen and        sulfur, and a 5-6 membered heteroaromatic fused ring having 1-3        heteroatoms independently selected from nitrogen, oxygen, and        sulfur; wherein said Ring B may be optionally substituted by one        or more oxo, thiono, or imino groups;    -   m is 0-4;    -   p is 0-2;    -   Q is —O— or —N(R)—    -   W is N or —C(R³)—;    -   R^(z) is —R, —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR, —C(O)R,        —N(R)₂, —N(R)C(O)OR, —N(R)C(O)N(R)₂, —OR, or —S(O)₂N(R)₂;    -   R³ is hydrogen, halogen, —CN, C₁₋₄ aliphatic, C₁₋₄        haloaliphatic, —OR, —C(O)R, or —C(O)N(R)₂;    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   each L² is independently a covalent bond or a C₁₋₆ bivalent        hydrocarbon chain wherein one or two methylene units of the        chain are optionally and independently replaced by —N(R)—,        —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—,        —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O)₂—; and    -   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,        —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,        —N(R)S(O)₂N(R)₂, —N(R)S(O)₂R, or an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur, or    -   two -L²(R⁴)_(p)—R⁴ groups are taken together with their        intervening atoms to form an optionally substituted 4-7 membered        fused, spiro, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;        as defined and described in WO 2014/011911 and US 2014/0018361,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and/or IRAK4 inhibitor

thereby forming a compound of formula I-vvv-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Q is CH, C—CN, or N;    -   X is C-L²(R⁴)_(p)—R^(x) and Y is N; or    -   X is N and Y is C-Rx;    -   Ring A is a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-7 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each R¹ and R^(1′) is independently —R², halogen, —CN, —NO₂,        —OR, —SR, —N(R)₂, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR,        —C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR, —N(R)C(O)N(R)₂, Cy, or        —N(R)S(O)₂R; or R¹ is selected from one of the following        formulas:

-   -   or two R¹ groups are taken together with their intervening atoms        to form an optionally substituted 4-7 membered fused,        spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each Cy is an optionally substituted ring selected from a 3-7        membered saturated or partially unsaturated carbocyclic ring or        a 4-10 membered saturated or partially unsaturated heterocyclic        ring having 1-3 heteroatoms independently selected from        nitrogen, oxygen, or sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, or sulfur;    -   each R² is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —N(R)₂,        —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂,        —N(R)C(O)R, —N(R)C(O)N(R)₂, —C(O)N(R)OR, —N(R)C(O)OR,        —N(R)S(O)₂N(R)₂, —N(R)S(O)₂R, or an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   R^(x) is hydrogen, —R², —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR,        —C(O)R, —N(R)₂, —NH[Ar], —OR, or —S(O)₂N(R)₂;    -   R^(z) is hydrogen, —R², —CN, —NO₂, halogen, —C(O)N(R)₂, —C(O)OR,        —C(O)R, —N(R)₂, —NH[Ar], —OR, or —S(O)₂N(R)₂;    -   [Ar] is a phenyl or heteroaromatic ring substituted by m        instances of R^(1′);    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   L² is a covalent bond or a C₁-6 bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   m is 0-4;    -   n is 0-4; and    -   p is 0-2;        as defined and described in WO 2015/048281 and US 2015/0094305,        the entirety of each of which is herein incorporated by        reference.

In some embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-vvv′-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   L and LBM are as defined above and described in embodiments        herein;    -   each A, B, C, D, E, F, G, H, X¹, X², and X³ are independently a        carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom;        and    -   each R¹, R², R³, and R⁴ are independently hydrogen or a        substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7        membered saturated or partially unsaturated heterocyclic having        1-2 heteroatoms independently selected from nitrogen, oxygen,        and sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   R¹ and R² and R³ and R⁴ are each optionally taken together            with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, independently selected from nitrogen,            oxygen, and sulfur.

Such IRAK4 inhibitors are well known to one of ordinary skill in the artand include those described in Scott et al., J. Med. Chem., 2017,60(24): 10071-10091 and Degorce et al., Bioorg. Med. Chem., 2018, 26(4):913-924.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-vvv′-2, I-vvv′-3, I-vvv′-4,I-vvv′-5, I-vvv′-6, I-vvv′-7, I-vvv′-8, I-vvv′-9, I-vvv′-10, I-vvv′-11,I-vvv′-12, I-vvv′-13, I-vvv′-14, I-vvv′-15, I-vvv′-16, I-vvv′-17,I-vvv′-18, I-vvv′-19, I-vvv′-20, I-vvv′-21, I-vvv′-22, I-vvv′-23,I-vvv′-24, I-vvv′-25, I-vvv′-26, I-vvv′-27, I-vvv′-28, I-vvv′-29,I-vvv′-30, I-vvv′-31, I-vvv′-32, I-vvv′-33, I-vvv′-34, I-vvv′-35,I-vvv′-36, I-vvv′-37, I-vvv′-38, and I-vvv′-39:

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   L and LBM are as defined above and described in embodiments        herein;        -   each X¹, X², and X³ are independently a carbon atom, a            nitrogen atom, an oxygen atom, or a sulfur atom; and    -   each R¹, R², R³, and R⁴ are independently hydrogen or a        substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7        membered saturated or partially unsaturated heterocyclic having        1-2 heteroatoms independently selected from nitrogen, oxygen,        and sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   R¹ and R² or R³ and R⁴ are optionally taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, independently selected from nitrogen, oxygen,            and sulfur.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK1 and/or IRAK4 inhibitor

thereby forming a compound of formula I-www-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   Q is ═N— or ═CH—;    -   Ring A is a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-7 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each R¹ is independently —R², halogen, —CN, —NO₂, —OR, —SR,        —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,        —C(O)N(R)OR, —N(R)C(O)OR, —N(R)C(O)NR₂, Cy, or —N(R)S(O)₂R; or        R¹ is selected from one of the following formulas:

-   -   or two R¹ groups are taken together with their intervening atoms        to form an optionally substituted 4-7 membered fused,        spiro-fused, or bridged bicyclic ring having 0-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each Cy is independently an optionally substituted ring selected        from a 3-7 membered saturated or partially unsaturated        carbocyclic ring or a 4-10 membered saturated or partially        unsaturated heterocyclic ring having 1-3 heteroatoms        independently selected from nitrogen, oxygen, or sulfur;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, or        sulfur, or 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or:    -   two R groups on the same nitrogen are taken together with their        intervening atoms to form a 4-7 membered saturated, partially        unsaturated, or heteroaryl ring having 0-3 heteroatoms, in        addition to the nitrogen, independently selected from nitrogen,        oxygen, or sulfur;    -   each R² is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, or sulfur;    -   each of R⁵ and R⁶ is independently hydrogen or        -L²(R⁴)_(p)—R^(x); or    -   R⁵ and R⁶ are taken together with their intervening atoms to        form a 4-7 membered partially unsaturated, or aromatic ring        having 0-3 heteroatoms independently selected from nitrogen,        oxygen, or sulfur;    -   each R⁴ is independently halogen, —CN, —NO₂, —OR, —SR, —NR₂,        —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,        —N(R)C(O)R, —N(R)C(O)NR₂, —C(O)N(R)OR, —N(R)C(O)OR,        —N(R)S(O)₂NR₂, —N(R)S(O)₂R, or an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, 4-7 membered saturated or        partially unsaturated heterocyclic having 1-2 heteroatoms        independently selected from nitrogen, oxygen, or sulfur, or 5-6        membered heteroaryl ring having 1-4 heteroatoms independently        selected from nitrogen, oxygen, and sulfur;    -   R^(x) is hydrogen, —R², —CN, —NO₂, halogen, —C(O)NR₂, —C(O)OR,        —C(O)R, —NR₂, —NH[Ar], —OR, or —S(O)₂NR₂;    -   R^(z) is hydrogen, —R², —CN, —NO₂, halogen, —C(O)NR₂, —C(O)OR,        —C(O)R, —NR₂, —NH[Ar], —OR, or —S(O)₂NR₂;    -   [Ar] is an optionally substituted phenyl or an optionally        substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms        independently selected from nitrogen, oxygen, and sulfur;    -   L¹ is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   L² is a covalent bond or a C₁₋₆ bivalent hydrocarbon chain        wherein one or two methylene units of the chain are optionally        and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—,        —N(R)S(O)₂—, —S(O)₂N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—,        —S(O)— or —S(O)₂—;    -   m is 0-4;    -   n is 0-4; and    -   p is 0-2;        as defined and described in WO 2015/164374 and US 2015/0329498,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor

thereby forming a compound of formula I-xxx-1

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X and X′ are each independently CR⁸, N or —N⁺—O⁻; Y is        independently N, —N⁺—O⁻ or CR^(8′) provided that at least one of        X, X′ or Y is neither N nor —N⁺—O⁻ and that no more than one of        X, X′ or Y is —N⁺—O⁻;    -   R¹ is C₁-C₆alkyl; C₂-C₆alkenyl; C₂-C₆alkynyl;        —(CR^(3a)R^(3b))_(m)-(3- to 7-membered cycloalkyl);        —(CR^(3a)R^(3b))_(m)-(3- to 7-membered heterocycloalkyl) having        one to three heteroatoms; —(CR^(3a)R^(3b))_(m)-(5- to        10-membered heteroaryl), having one to three heteroatoms; or        —(CR^(3a)R^(3b))_(m)—C₆-C₁₂aryl; wherein said alkyl, alkenyl,        alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is        optionally substituted with one to five halogen, deuterium,        —OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl        or —C₁-C₆alkoxy;    -   R² is —(CR^(3a)R^(3b))_(m)-(3- to 10-membered cycloalkyl);        —(CR^(3a)R^(3b))_(m)-(3- to 10-membered heterocycloalkyl) having        one to three heteroatoms; —(CR^(3a)R^(3b))_(m)-(5- to 10        membered heteroaryl) having one to three heteroatoms; or        —(CR^(3a)R^(3b))—C₆-C₁₂aryl; wherein said cycloalkyl,        heterocycloalkyl, heteroaryl or aryl is optionally substituted        with one to five R⁴; and wherein, if the heteroatom on said        heterocycloalkyl and heteroaryl is N, said N is    -   optionally substituted with R^(4′); or R² is C₁-C₆alkyl, wherein        said alkyl is optionally substituted with NH₂, OH or cyano;    -   R^(3a) and R^(3b) for each occurrence are independently hydrogen        or C₁-C₃alkyl;    -   R⁴ for each occurrence is independently a bond, deuterium        halogen, cyano, C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵, —SR⁵,        —S(O)R⁹, —S(O)₂R⁹, —NR^(11a)R^(11b), —C(O)R¹⁰,        —(CR^(3a)R^(3b))_(n)(3- to 7-membered cycloalkyl),        —(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl),        having one to three heteroatoms, —(CR^(3a)R^(3b))_(n)-(5- to 10        membered heteroaryl), having one to three heteroatoms, or        —(CR^(3a)R^(3b))_(n) C₆-C₁₂aryl wherein said alkyl, cycloalkyl,        heterocycloalkyl, heteroaryl or aryl is each optionally and        independently substituted with one to five deuterium, halogen,        OR⁵, —SR⁵, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl        or —C₁-C₆alkoxy; or two R⁴ taken together with the respective        carbons to which each are bonded form a 3- to 6-membered        cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said        cycloalkyl or heterocycloalkyl is optionally substituted with        one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),        cyano or C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy        is optionally substituted with halogen, deuterium, —OR⁵, —SR⁵,        —NR^(11a)R^(11b) or cyano; and wherein, if a heteroatom on said        heterocycloalkyl is N, said N is optionally substituted with        R^(4′);    -   R^(4′) is independently C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁰,        —S(O)₂R⁹, —(CR^(3a)R^(3b))_(n)-(3- to 7-membered cycloalkyl),        —(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl) or        C(O)(CH₂)_(t)CN; wherein said alkyl, alkenyl, cycloalkyl, or        heterocycloalkyl is each optionally and independently        substituted with one to five deuterium, halogen, OH, cyano or        C₁-C₆alkoxy; or R⁴ and R^(4′) taken together with the respective        atoms to which each are bonded form a 3- to 6-membered        cycloalkyl or 4- to 6-membered heterocycloalkyl, wherein said        cycloalkyl or heterocycloalkyl is optionally substituted with        one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),        cyano, C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy is        optionally substituted with halogen, deuterium, —OR⁵, —SR⁵,        —NR^(11a)R^(11b), or cyano; R⁵ is independently hydrogen or        C₁-C₆alkyl, wherein said alkyl is optionally substituted with        halogen, deuterium, C₁-C₆alkoxy, C₁-C₆alkylthiolyl,        —NR^(11a)R^(11b) cyano, C₁-C₆alkyl or C₃-C₆cycloalkyl; or two R⁵        taken together with the oxygen atoms to which they are bonded        form a 5- or 6-membered heterocycloalkyl;    -   R⁶ is —C(O)NHR⁷, CO₂R⁷ or cyano;    -   R⁷ is hydrogen or C₁-C₆alkyl;    -   each R⁸ is independently hydrogen, halogen, cyano, —OR⁵, —SR⁵,        —NR^(11a)R^(11b), C₆alkyl, C₃-C₆cycloalkyl, 3- to 10-membered        heterocycloalkyl or 5- to 6-membered heteroaryl or aryl, wherein        said alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl is        optionally substituted with one to three halogen,        —NR^(11a)R^(11b), OR⁵, —SR⁵, cyano, C₁-C₃ alkyl, —C(O)R¹⁰ or        oxo;    -   R^(8′) is hydrogen, deuterium, halogen, cyano, —OR⁵, —SR⁵ or        NR^(11a)R^(11b);    -   R⁹ is —(CR^(3a)R^(3b))_(p)—(C₁-C₃alkyl),        —(CR^(3a)R^(3b))_(p)-(4- to 6-membered cycloalkyl),        —(CR^(3a)R^(3b))_(p)-(4- to 6-membered heterocycloalkyl) or        —(CR^(3a)R^(3b))_(p)—(C₅-C₉aryl), wherein said alkyl,        cycloalkyl, heterocycloalkyl or aryl are each optionally        substituted with fluoro or C₁-C₃alkyl;    -   R¹⁰ is C₁-C₆alkyl, wherein said alkyl is optionally substituted        with deuterium, halogen, OH, C₁-C₆alkoxy or cyano;    -   R^(11a) and R^(11b) are each independently hydrogen or        C₁-C₆alkyl, wherein said alkyl is optionally substituted with        deuterium, C₁-C₆alkoxy or cyano; and if C₂-C₆alkyl, said alkyl        is optionally substituted with deuterium, C₁-C₆alkoxy, cyano,        halogen or OH;    -   m is independently 0, 1, 2 or 3;    -   n is independently 0, 1, 2 or 3;    -   p is independently 0 or 1; and    -   t is 1, 2 or 3;        as defined and described in WO 2015/150995 and US 2015/0284405,        the entirety of each of which is herein incorporated by        reference.

In certain embodiments, the present invention provides a compound ofFormula I, wherein IRAK is an IRAK4 inhibitor or

thereby forming a compound of formula I-yyy-1 or I-yyy-2:

-   -   or a pharmaceutically acceptable salt thereof, wherein L and LBM        are as defined above and described in embodiments herein, and        wherein:    -   X is N or CH    -   m is 1 or 2;    -   Ar is optionally substituted aryl or optionally substituted        heteroaryl;    -   R¹ is hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, hydroxyl,        hydroxy-C₁₋₆alkyl, C₁₋₆alkyl-amino, amino-C₁₋₆alkyl,        amino-C₁₋₆alkyl-amino, hydroxy-C₁₋₆alkylamino,        C₃₋₆cycloalkylamino, amino-C₃₋₆ cycloalkylamino,        amino-C₃₋₆heterocycloalkylamino, aminocarbonyl, halo,        hydroxy-C₁₋₆alkyl, or hydroxy-C₁₋₆alkoxy; and    -   R² is hydrogen or C₁₋₆alkyl;        as defined and described in WO 2012/007375 and US 2012/0015962,        the entirety of each of which is herein incorporated by        reference.

As defined above and described herein, IRAK is an IRAK binding moietycapable of binding to one or more of IRAK-1, -2, -3, or -4.

In some embodiments, IRAK is an IRAK binding moiety capable of bindingto IRAK-1. In some embodiments, IRAK is an IRAK binding moiety capableof binding to IRAK-2. In some embodiments, IRAK is an IRAK bindingmoiety capable of binding to IRAK-3. In some embodiments, IRAK is anIRAK binding moiety capable of binding to IRAK-4.

In some embodiments, IRAK is selected from a moiety recited in AurigeneDiscovery Tech. Ltd. Presentation: Novel IRAK-4 Inhibitors exhibithighly potent anti-proliferative activity in DLBCL cell lines withactivation MYD88 L264P mutation, such as, for example: AU-5850, AU-2807,AU-6686, and AU-5792, wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Scott, J.S. et al. Discovery and Optimization of Pyrrolopyrimidine Inhibitors ofInterleukin-I Receptor Associated Kinase 4 (IRAK4) for the Treatment ofMutant MYD88 Diffuse Large B-cell Lymphoma. J. Med. Chem. Manuscript,Nov., 29, 2017, 10.1021/acs.jmedchem.7b01290 such as, for example:

-   -   wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Powers,J. P. et al., Discovery and initial SAR of inhibitors of interleukin-Ireceptor-associated kinase-4, Bioorg. Med Chem Lett. (2006) 16(11):2842-45, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Wang, etal., Crystal Structure of IRAK-4 Kinase in Complex with Inhibitors:Serine/Threonine Kinase with Tyrosine as a Gatekeeper, Structure, 2006,14(12): 1835-44, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Wang, Z.et al., Discovery of potent, selective, and orally bioavailableinhibitors of interleukin-I receptor-associated kinase 4, Bioorg. Med.Chem Lett., 2015, 25(23): 5546-50, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited inChaudhary, D. et al., Recent Advances in the Discovery of Small MoleculeInhibitors of Interleukin-I Receptor-Associated Kinase 4 (IRAK4) as aTherapeutic Target for Inflammation and Oncology Disorders, J. MedChem., 2015, 58(1): 96-110, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Zhang, D.et al., Constitutive IRAK4 Activation Underlies Poor Prognosis andChemoresistance in Pancreatic Ductal Adenocarcinoma, Clin. Can. Res.,2017, 23(7): 1748-59, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Cushing,L. et al., IRAK4 kinase controls Toll-like receptor induced inflammationthrough the transcription factor IRF5 in primary human monocytes, J.Bio. Chem., 2017, 292(45): 18689-698, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Li, N. etal., Targeting interleukin-I receptor-associated kinase for humanhepatocellular carcinoma, J. Ex. Clin. Can. Res., 2016, 35(1): 140-50,such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited inDudhgaonkar, S. et al., Selective IRAK4 Inhibition Attenuates Disease inMurine Lupus Models and Demonstrates Steroid Sparing Activity, J. ofImmun., 2017, 198(3): 1308-19, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Wang, Z.et al., IRAK-4 Inhibitors for Inflammation, Cur. Top. Med. Chem., 2009,9(8): 724-37, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Kelly, P.N. et al., Selective interleukin-I receptor-associated kinase 4inhibitors for the treatment of autoimmune disorders and lymphoidmalignancy, J. Exp. Med., 2015, 212(13): 2189-201, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Dunne, A.et al., IRAK1 and IRAK4 Promote Phosphorylation, Ubiquitation, andDegradation of MyD88 Adaptor-like (Mal), J. Bio. Chem., 2010, 285(24):18276-82, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Küppers,R., IRAK inhibition to shut down TLR signaling in autoimmunity andMyD88-dependent lymphomas, J. Exp. Med, 2015, 212(13): 2184, such as,for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Chiang,E. Y. et al., Immune Complex-Mediated Cell Activation from SystemicLupus Erythematosus and Rheumatoid Arthritis Patients ElaborateDifferent Requirements forIRAK1/4 Kinase Activity across human CellTypes, J. Immunol., 2011, 186(2): 1279-88, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Lee, K.L. et al., Discovery of Clinical Candidate1-{[2S,3S,4S)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoine-6-carboxamide(PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 ReceptorAssociated Kinase 4 9IRAK4), by Fragment-Based Drug Design, J. Med.Chem., 2017, 60(13): 5521-42, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Kondo, M.et al., Renoprotective effects of novel interleukin-1receptor-associated kinase 4 inhibitor AS2444697 throughanti-inflammatory action in 5/6 nephrectomized rats,Naunyn-Schmiedeberg's Arch Pharmacol., 2014, 387(10): 909-19, such as,for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Song, K.W. et al., The Kinase activities of interleukin-I receptor associatedkinase (IRAK)-1 and 4 are redundant in the control of inflammatorycytokine expression in human cells, Mol. Immunol., 2009, 46(7): 1458-66,such as, for example: R00884, R01679, or R06245, wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is selected from a moiety recited in Vollmer,S. et al., The mechanism of activation of IRAK1 and IRAK4 byinterleukin-1 and Toll-like receptor agonists, Biochem. J., 2017,474(12): 2027-38, such as, for example: IRAK-IN-1A, JNK-IN-7, andJNK-IN-8, wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, an IRAK ligand is selected from moiety recited inMcElroy, W. T., et al., Potent and Selective Amidopyrazole Inhibitors ofIRAK4 That Are Efficacious in a Rodent Model of Inflammation, Med. Chem.Lett., 2015, 6(6): 677-82, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, an IRAK ligand is selected from moiety recited inSeganish, W. M., et al., Discovery and Structure Enabled Synthesis of2,6-diaminopyrimidine-4-one IRAK4 Inhibitors, Med. Chem. Lett., 2015,6(8): 942-47, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, an IRAK ligand is selected from moiety recited inSeganish, W. M., et al., Initial optimization and series evolution ofdiaminopyrimidine inhibitors of interleukin-1 receptor associated kinase4, Bioorg. Med. Chem. Lett., 2015, 25(16): 3203-207, such as, forexample:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, an

In some embodiments, IRAK is

In some IRAK ligand is selected from moiety recited in McElroy, W. T.,et al., Discovery and hit-to-lead optimization of 2,6-diaminopyrimidineInhibitors of interleukin-1 receptor-associated kinase 4, Bioorg. Med.Chem. Lett., 2015, 25(9): 1836-41, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, an IRAK ligand is selected from moiety recited inTumey, L. N., et al., Identification and optimization ofindolo[2,3-c]quinoline inhibitors of IRAK4, Bioorg. Med. Chem. Lett.,2014, 24(9): 2066-72, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is

In some embodiments, IRAK is selected from those depicted in Table 1,below.

As defined above and described herein, L is a bivalent moiety thatconnects IRAK to LBM.

In some embodiments, L is a bivalent moiety that connects IRAK to LBM.

In some embodiments, L is a covalent bond or a bivalent, saturated orunsaturated, straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6methylene units of L are independently replaced by -Cy-, —O—, —NR—, —S—,—OC(O)—, —C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—, —S(O)₂NR—,—NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein: each -Cy- is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-7membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-7 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclicheteroarylenyl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, each -Cy- is independently an optionallysubstituted bivalent phenylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 8-10 membered bicyclic arylenyl.In some embodiments, each -Cy- is independently an optionallysubstituted 4-7 membered saturated or partially unsaturatedcarbocyclylenyl. In some embodiments, each -Cy- is independently anoptionally substituted 4-7 membered saturated or partially unsaturatedspiro carbocyclylenyl. In some embodiments, each -Cy- is independentlyan optionally substituted 8-10 membered bicyclic saturated or partiallyunsaturated carbocyclylenyl. In some embodiments, each -Cy- isindependently an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclylenyl having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, each -Cy- is independently an optionally substituted 4-7membered saturated or partially unsaturated spiro heterocyclylenylhaving 1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, each -Cy- isindependently an optionally substituted 5-6 membered heteroarylenylhaving 1-4 heteroatoms independently selected from nitrogen, oxygen, andsulfur. In some embodiments, each -Cy- is independently an optionallysubstituted 8-10 membered bicyclic heteroarylenyl having 1-5 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In some embodiments, -Cy- is

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In some embodiments, L is selected from those depicted in Table 1,below.

As defined above and described herein, LBM is a ligase binding moiety.

In some embodiments, LBM is LBM is an E3 ubiquitin ligase (cereblon)binding moiety

a DCAF15 E3 ubiquitin ligase binding moiety

or a VHL E3 ubiquitin ligase binding moiety

-   -   wherein each of X¹, X², and X³ is independently a bivalent        moiety selected from a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

-   -   each of X⁴ and X⁵ is independently a bivalent moiety selected        from —CH₂—, —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic;    -   each of R², R³, and R⁴ is independently hydrogen, —R⁶, halogen,        —CN, —NO₂, —OR, —SR, —NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)NR₂, —C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)NR₂, or —N(R)S(O)₂R;    -   R⁵ is hydrogen or C₁₋₆ aliphatic;    -   each R⁶ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring A is a fused ring selected from 6-membered aryl containing        0-2 nitrogen atoms, 5 to 7-membered partially saturated        carbocyclyl, 5 to 7-membered partially saturated heterocyclyl        with 1-2 heteroatoms independently selected from nitrogen,        oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   Ring B is selected from 6-membered aryl containing 0-2 nitrogen        atoms or a 8-10 membered bicyclic heteroaryl having 1-5        heteroatoms independently selected from nitrogen, oxygen, or        sulfur;    -   Ring C is a selected from 6-membered aryl containing 0-2        nitrogen atoms or a 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   m is 0, 1, 2, 3 or 4;    -   each of n is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;    -   p is 0, 1, 2, 3 or 4;    -   q is 0, 1, 2, 3 or 4; and    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are optionally taken            together with their intervening atoms to form a 4-7 membered            saturated, partially unsaturated, or heteroaryl ring having            0-3 heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur.

In some embodiments, LBM is

In some embodiments, LBM is

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In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is a E3 Ubiquitin ligase (cereblon) bindingmoiety recited in Varfolomeev, E. et al., IAP Antagonists InduceAutoubiquitination of c-IAPs, NF-κB activation, and TNFa-DependentApoptosis, Cell, 2007, 131(4): 669-81, such as, for example:

wherein

is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom.

In some embodiments, LBM is selected from those depicted in Table 1,below.

As defined above and described herein, each of X¹, X², and X³ isindependently a bivalent moiety selected from a covalent bond, —CH₂—,—C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X¹ is selected from those depicted in Table 1,below.

In some embodiments, X² is a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X² is selected from those depicted in Table 1,below.

In some embodiments, X³ is a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X³ is selected from those depicted in Table 1,below.

As defined above and described herein, each of X⁴ and X⁵ isindependently a bivalent moiety selected from —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X⁴ is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X⁴ is selected from those depicted in Table 1,below.

In some embodiments, X⁵ is —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X⁵ is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, or an optionallysubstituted C₁₋₄ aliphatic.

In some embodiments, R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR,—S(O)R, —S(O)₂R, —NR₂, or an optionally substituted C₁₋₄ aliphatic.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each of R², R³, and R⁴ isindependently hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR, —NR₂,—S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂, —C(O)N(R)OR,—OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂, or—N(R)S(O)₂R.

In some embodiments, R² is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R² is selected from those depicted in Table 1,below.

In some embodiments, R³ is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R³ is methyl.

In some embodiments, R³ is selected from those depicted in Table 1,below.

In some embodiments, R⁴ is hydrogen, —R⁶, halogen, —CN, —NO₂, —OR, —SR,—NR₂, —S(O)₂R, —S(O)₂NR₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR₂,—C(O)N(R)OR, —OC(O)R, —OC(O)NR₂, —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR₂,or —N(R)S(O)₂R.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁴ is selected from those depicted in Table 1,below.

As defined above and described herein, R⁵ is hydrogen or C₁₋₆ aliphatic.

In some embodiments, R⁵ is t-butyl.

In some embodiments, R⁵ is selected from those depicted in Table 1,below.

As defined above and described herein, each R⁶ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R⁶ is an optionally substituted C₁₋₆ aliphaticgroup. In some embodiments, R⁶ is an optionally substituted phenyl. Insome embodiments, R⁶ is an optionally substituted 4-7 membered saturatedor partially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R⁶ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R⁶ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a fused ring selectedfrom 6-membered aryl containing 0-2 nitrogen atoms, 5 to 7-memberedpartially saturated carbocyclyl, 5 to 7-membered partially saturatedheterocyclyl with 1-2 heteroatoms independently selected from nitrogen,oxygen or sulfur, or 5-membered heteroaryl with 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments Ring A is a fused 6-membered aryl containing 0-2nitrogen atoms. In some embodiments Ring A is a fused 5 to 7-memberedpartially saturated carbocyclyl. In some embodiments Ring A is a fused 5to 7-membered partially saturated heterocyclyl with 1-2 heteroatomsindependently selected from nitrogen, oxygen or sulfur. In someembodiments Ring A is a fused 5-membered heteroaryl with 1-3 heteroatomsindependently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring A is a fused phenyl.

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, Ring B is selected from6-membered aryl containing 0-2 nitrogen atoms or a 8-10 memberedbicyclic heteroaryl having 1-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur.

In some embodiments, Ring B is a 6-membered aryl containing 0-2 nitrogenatoms. In some embodiments, Ring B is a 8-10 membered bicyclicheteroaryl having 1-5 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

In some embodiments, Ring B is

In some embodiments, Ring B is selected from those depicted in Table 1,below.

As defined above and described herein, Ring C is selected from6-membered aryl containing 0-2 nitrogen atoms or a 5-membered heteroarylwith 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, Ring C is a 6-membered aryl containing 0-2 nitrogenatoms. In some embodiments, Ring C is a 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring C is

In some embodiments, Ring C is selected from those depicted in Table 1,below.

As defined above and described herein, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined above and described herein, each of n is independently 1, 2,3, 4, 5, 6, 7, 8, 9, or 10.

In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4. In some embodiments, n is 5. In some embodiments, n is 6. In someembodiments, n is 7. In some embodiments, n is 8. In some embodiments, nis 9. In some embodiments, n is 10.

In some embodiments, n is selected from those depicted in Table 1,below.

As defined above and described herein, p is 0, 1, 2, 3 or 4.

In some embodiments, p is 0. In some embodiments, p is 1. In someembodiments, p is 2. In some embodiments, p is 3. In some embodiments, pis 4.

In some embodiments, p is selected from those depicted in Table 1,below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In someembodiments, q is 2. In some embodiments, q is 3. In some embodiments, qis 4.

In some embodiments, q is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are optionally taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is phenyl. Insome embodiments, R is a 4-7 membered saturated or partially unsaturatedheterocyclic having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 memberedheteroaryl ring having 1-4 heteroatoms independently selected fromnitrogen, oxygen, and sulfur. In some embodiments, two R groups on thesame nitrogen are optionally taken together with their intervening atomsto form a 4-7 membered saturated, partially unsaturated, or heteroarylring having 0-3 heteroatoms, in addition to the nitrogen, independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-zzz:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   X² is a carbon atom or silicon atom;    -   X³ is a bivalent moiety selected from —CH₂— or —Si(R₂)—;    -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,        —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;    -   each R³ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring A is a tricyclic ring selected from

wherein

-   -   each of Ring B, Ring C, and Ring D is independently a fused ring        selected from 6-membered aryl containing 0-3 nitrogens, 5 to        7-membered saturated or partially unsaturated carbocyclyl, 5 to        7-membered saturated or partially unsaturated heterocyclyl ring        with 1-3 heteroatoms independently selected from boron,        nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl        with 1-3 heteroatoms independently selected from nitrogen,        oxygen or sulfur; and    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16;    -   wherein L and IRAK are as described in embodiments herein.

In some embodiments, a compound of formula I-zzz above is provided as acompound of formula I-zzz′ or formula I-zzz″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, L, R¹, R², X¹, and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-aaaa:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,        —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;    -   each R³ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring A is a tricyclic ring selected from

wherein

-   -   each of Ring B, Ring C, and Ring D is independently a fused ring        selected from 6-membered aryl containing 0-3 nitrogens, 5 to        7-membered saturated or partially unsaturated carbocyclyl, 5 to        7-membered saturated or partially unsaturated heterocyclyl ring        with 1-3 heteroatoms independently selected from boron,        nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl        with 1-3 heteroatoms independently selected from nitrogen,        oxygen or sulfur; and    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16;    -   wherein L and IRAK are as described in embodiments herein.

In some embodiments, a compound of formula I-aaaa above is provided as acompound of formula I-aaaa′ or formula I-aaaa″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, L, R¹, R², X¹, and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-bbbb:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,        —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;    -   each R³ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring A is a tricyclic ring selected from

wherein

-   -   each of Ring B and Ring C is independently a fused ring selected        from 6-membered aryl containing 0-3 nitrogens, 5 to 7-membered        saturated or partially unsaturated carbocyclyl, 5 to 7-membered        saturated or partially unsaturated heterocyclyl ring with 1-3        heteroatoms independently selected from boron, nitrogen, oxygen        or sulfur, or 5-membered heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   Ring D is a fused ring selected from aryl containing 0-3        nitrogens, saturated or partially unsaturated carbocyclyl,        saturated or partially unsaturated heterocyclyl ring with 1-2        heteroatoms independently selected from nitrogen, oxygen,        silicon, or sulfur, or heteroaryl with 1-3 heteroatoms        independently selected from nitrogen, oxygen or sulfur;    -   is a single or double bond;    -   m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or        16;        -   wherein L and IRAK are as described in embodiments herein.

In some embodiments, a compound of formula I-bbbb above is provided as acompound of formula I-bbbb′ or formula I-bbbb″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, L, R¹, R², X¹, and m is as defined above.

As described above, in certain embodiments, the present inventionprovides a compound of formula I-cccc:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X¹ is a bivalent moiety selected from a covalent bond, —CH₂—,        —C(O)—, —C(S)—, or

-   -   R¹ is hydrogen, deuterium, halogen, —CN, —OR, —SR, —S(O)R,        —S(O)₂R, —N(R)₂, —Si(R)₃, or an optionally substituted C₁₋₄        aliphatic;    -   each R is independently hydrogen, or an optionally substituted        group selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered        saturated or partially unsaturated heterocyclic having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, or:        -   two R groups on the same nitrogen are taken together with            their intervening atoms to form a 4-7 membered saturated,            partially unsaturated, or heteroaryl ring having 0-3            heteroatoms, in addition to the nitrogen, independently            selected from nitrogen, oxygen, and sulfur;    -   each R² is independently hydrogen, —R³, halogen, —CN, —NO₂, —OR,        —SR, —N(R)₂, —Si(R)₃, —S(O)₂R, —S(O)₂N(R)₂, —S(O)R, —C(O)R,        —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR, —C(R)₂N(R)C(O)R,        —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,        —N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R;    -   each R³ is independently an optionally substituted group        selected from C₁₋₆ aliphatic, phenyl, a 4-7 membered saturated        or partially unsaturated heterocyclic ring having 1-2        heteroatoms independently selected from nitrogen, oxygen, and        sulfur, and a 5-6 membered heteroaryl ring having 1-4        heteroatoms independently selected from nitrogen, oxygen, and        sulfur;    -   Ring A is a tricyclic ring selected from

wherein

-   -   each of Ring B and Ring C is independently a fused ring selected        from 6-membered aryl containing 0-2 nitrogens, 5 to 7-membered        saturated or partially unsaturated carbocyclyl, 5 to 7-membered        saturated or partially unsaturated heterocyclyl ring with 1-3        heteroatoms independently selected from boron, nitrogen, oxygen,        silicon, or sulfur, or 5-membered heteroaryl with 1-3        heteroatoms independently selected from nitrogen, oxygen or        sulfur;    -   is a single or double bond;    -   m is 0, 1, 2, 3, 4, 5, 6, 7, or 8;        -   wherein L and IRAK are as described in embodiments herein.

In some embodiments, a compound of formula I-ecce above is provided as acompound of formula I-cccc′ or formula I-cccc″:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   each of IRAK, Ring A, L, R¹, R², X¹, and m is as defined above.

As defined above and described herein, X¹ is a bivalent moiety selectedfrom a covalent bond, —CH₂—, —C(O)—, —C(S)—, or

In some embodiments, X¹ is a covalent bond. In some embodiments, X¹ is—CH₂—. In some embodiments, X¹ is —C(O)—. In some embodiments, X¹ is—C(S)—. In some embodiments, X¹ is

In some embodiments, X¹ is selected from those depicted in Table 1,below.

As defined above and described herein, X² is a carbon atom or siliconatom.

In some embodiments, X² is a carbon atom. In some embodiments, X² is asilicon atom.

In some embodiments, X² is selected from those depicted in Table 1,below.

As defined above and described herein, X³ is a bivalent moiety selectedfrom —CH₂— or —Si(R₂)—.

In some embodiments, X³ is —CH₂—. In some embodiments, X² is —Si(R₂)—.

In some embodiments, X³ is selected from those depicted in Table 1,below.

As defined above and described herein, R¹ is hydrogen, deuterium,halogen, —CN, —OR, —SR, —S(O)R, —S(O)₂R, —NR₂, —Si(R₃), or an optionallysubstituted C₁₋₄ aliphatic.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ isdeuterium. In some embodiments, R¹ is halogen. In some embodiments, R¹is —CN. In some embodiments, R¹ is —OR. In some embodiments, R¹ is —SR.In some embodiments, R¹ is —S(O)R. In some embodiments, R¹ is —S(O)₂R.In some embodiments, R¹ is —NR₂. In some embodiments, R¹ is —Si(R₃). Insome embodiments, R¹ is an optionally substituted C₁₋₄ aliphatic.

In some embodiments, R¹ is selected from those depicted in Table 1,below.

As defined above and described herein, each R is independently hydrogen,or an optionally substituted group selected from C₁₋₆ aliphatic, phenyl,a 4-7 membered saturated or partially unsaturated heterocyclic having1-2 heteroatoms independently selected from nitrogen, oxygen, andsulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, and sulfur, or: two Rgroups on the same nitrogen are taken together with their interveningatoms to form a 4-7 membered saturated, partially unsaturated, orheteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen,independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is optionallysubstituted C₁₋₆ aliphatic. In some embodiments, R is optionallysubstituted phenyl. In some embodiments, R is optionally substituted 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur. Insome embodiments, R is optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur. In some embodiments, two R groups on the samenitrogen are taken together with their intervening atoms to form a 4-7membered saturated, partially unsaturated, or heteroaryl ring having 0-3heteroatoms, in addition to the nitrogen, independently selected fromnitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1,below.

As defined above and described herein, each R² is independentlyhydrogen, —R³, halogen, —CN, —NO₂, —OR, —SR, —N(R)₂, —Si(R₃), —S(O)₂R,—S(O)₂N(R)₂, —S(O)R, —C(O)R, —C(O)OR, —C(O)N(R)₂, —C(O)N(R)OR,—C(R)₂N(R)C(O)R, —C(R)₂N(R)C(O)N(R)₂, —OC(O)R, —OC(O)N(R)₂, —N(R)C(O)OR,—N(R)C(O)R, —N(R)C(O)N(R)₂, or —N(R)S(O)₂R.

In some embodiments, R² is hydrogen. In some embodiments, R² is —R³. Insome embodiments, R² is halogen. In some embodiments, R² is —CN. In someembodiments, R² is —NO₂. In some embodiments, R² is —OR. In someembodiments, R² is —SR. In some embodiments, R² is —NR₂. In someembodiments, R² is —Si(R₃). In some embodiments, R² is —S(O)₂R. In someembodiments, R² is —S(O)₂NR₂. In some embodiments, R² is —S(O)R. In someembodiments, R² is —C(O)R. In some embodiments, R² is —C(O)OR. In someembodiments, R² is —C(O)NR₂. In some embodiments, R² is —C(O)N(R)OR. Insome embodiments, R² is —C(R)₂N(R)C(O)R. In some embodiments, R² is—C(R)₂N(R)C(O)N(R)₂. In some embodiments, R² is —OC(O)R. In someembodiments, R² is —OC(O)NR₂. In some embodiments, R² is —N(R)C(O)OR. Insome embodiments, R² is —N(R)C(O)R. In some embodiments, R² is—N(R)C(O)NR₂. In some embodiments, R² is —N(R)S(O)₂R.

In some embodiments, R² is selected from those depicted in Table 1,below.

As defined above and described herein, each R³ is independently anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur.

In some embodiments, R³ is an optionally substituted C₁₋₆ aliphatic. Insome embodiments, R³ is an optionally substituted phenyl. In someembodiments, R³ is an optionally substituted 4-7 membered saturated orpartially unsaturated heterocyclic ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, and sulfur. In someembodiments, R³ is an optionally substituted 5-6 membered heteroarylring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur.

In some embodiments, R³ is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, each of Ring B, Ring C, and RingD is independently a fused ring selected from 6-membered aryl containing0-3 nitrogens, 5 to 7-membered saturated or partially unsaturatedcarbocyclyl, 5 to 7-membered saturated or partially unsaturatedheterocyclyl ring with 1-3 heteroatoms independently selected fromboron, nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroarylwith 1-3 heteroatoms independently selected from nitrogen, oxygen orsulfur.

In some embodiments, each Ring B, Ring C, and Ring D is independently a6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, eachRing B, Ring C, and Ring D is independently a 5 to 7-membered saturatedor partially unsaturated carbocyclyl. In some embodiments, each Ring B,Ring C, and Ring D is independently a 5 to 7-membered saturated orpartially unsaturated heterocyclyl with 1-2 heteroatoms independentlyselected from boron, nitrogen, oxygen, silicon, or sulfur. In someembodiments, each Ring B, Ring C, and Ring D is independently a5-membered heteroaryl with 1-3 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, Ring B, Ring C, and Ring D is selected from thosedepicted in Table 1, below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiment, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, Ring D is a fused ring selectedfrom aryl containing 0-3 nitrogens, saturated or partially unsaturatedcarbocyclyl, saturated or partially unsaturated heterocyclyl ring with1-2 heteroatoms independently selected from nitrogen, oxygen, silicon,or sulfur, or heteroaryl with 1-3 heteroatoms independently selectedfrom nitrogen, oxygen or sulfur.

In some embodiments, Ring D is an aryl containing 0-2 nitrogen atoms. Insome embodiments, Ring D is a saturated or partially unsaturatedcarbocyclyl. In some embodiments, each Ring D is a saturated orpartially unsaturated heterocyclyl with 1-2 heteroatoms independentlyselected from nitrogen, oxygen, silicon, or sulfur. In some embodiments,Ring D is a heteroaryl with 1-3 heteroatoms independently selected fromnitrogen, oxygen or sulfur.

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is

In some embodiments, Ring D is selected from those depicted in Table 1,below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8. In some embodiments, mis 9. In some embodiments, m is 10. In some embodiments, m is 11. Insome embodiments, m is 12. In some embodiments, m is 13. In someembodiments, m is 14. In some embodiments, m is 15. In some embodiments,m is 16.

In some embodiments, m is selected from those depicted in Table 1,below.

As defined above and described herein, Ring A is a tricyclic ringselected from

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiment, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1,below.

As defined above and described herein, each Ring B and Ring C isindependently a fused ring selected from 6-membered aryl containing 0-2nitrogen atoms, 5 to 7-membered saturated or partially unsaturatedcarbocyclyl, 5 to 7-membered saturated or partially unsaturatedheterocyclyl with 1-3 heteroatoms independently selected from boron,nitrogen, oxygen, silicon, or sulfur, or 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring B and Ring C is independently a6-membered aryl containing 0-2 nitrogen atoms. In some embodiments, eachRing B and Ring C is independently a 5 to 7-membered saturated orpartially unsaturated carbocyclyl. In some embodiments, each Ring B andRing C is independently a 5 to 7-membered saturated or partiallyunsaturated heterocyclyl with 1-3 heteroatoms independently selectedfrom boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments,each Ring B and Ring C is independently a 5-membered heteroaryl with 1-3heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, each Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently is

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently

In some embodiments, Ring B and Ring C is independently selected fromthose depicted in Table 1, below.

As defined above and described herein,

is a single or double bond

In some embodiments,

is a single bond. In some embodiments,

is a double bond.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, or8.

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3. In some embodiments, mis 4. In some embodiments, m is 5. In some embodiments, m is 6. In someembodiments, m is 7. In some embodiments, m is 8.

In some embodiments, m is selected from those depicted in Table 1,below.

In some embodiments, In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In some embodiments, LBM is

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety

-   -   thereby forming a compound of formula I-dddd:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables R⁹, R¹⁰, R¹¹, R^(14a), and R¹⁵ is as described and definedin WO 2017/030814, WO 2016/118666, and US 2017/0327469, the entirety ofeach of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a VHL binding moiety

-   -   thereby forming a compound of formula I-eeee:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables X, R⁹, R¹⁰, R¹¹, R^(14a), and R¹⁵ is as described anddefined in WO 2017/030814, WO 2016/118666, and US 2017/0327469, theentirety of each of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is an IAP binding moiety

or derivative thereof;thereby forming a compound of formula I-ffff:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein each ofthe variables W, Y, Z, R¹, R², R³, R⁴, and R⁵ is as described anddefined in WO 2014/044622, US 2015/0225449. WO 2015/071393, and US2016/0272596, the entirety of each of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a MDM2 binding moiety

or derivatives thereof;thereby forming a compound of formula I-gggg:

or derivative thereof, or a pharmaceutically acceptable salt thereof, asdescribed and defined in Hines, J. et al., Cancer Res. (DOI:10.1158/0008-5472.CAN-18-2918), the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a DCAF16 binding moiety

or derivatives thereof;thereby forming a compound of formula I-hhhh:

or derivative thereof, or a pharmaceutically acceptable salt thereof, asdescribed and defined in Zhang, X. et al., bioRxiv (doi:https://doi.org/10.1101/443804), the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF114 binding moiety

or derivatives thereof;thereby forming a compound of formula I-iiii:

or derivative thereof, or a pharmaceutically acceptable salt thereof, asdescribed and defined in Spradin, J. N. et al., bioRxiv (doi:https://doi.org/10.1101/436998), the entirety of each of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-jjjj:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein X, Y, R₁,R₂, and R₃ are as defined and described in WO 2018/209012, the entiretyof which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-kkkk:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein R₁, R₂,R₃, R₄, R₅, R₆, and R₇ are as defined and described in US 2018/0230157,the entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK1 and/or IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-llll:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein Ring A1,Ring B, Ring C, L^(1A), R¹, R², R³, R⁴, n, and p are as defined anddescribed in WO 2018/098367, the entirety of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-mmmm:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein R¹, R²,R³, R⁴, R⁵, and R⁶ are as defined and described in WO 2018/052058, theentirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK1 and/or IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-nnnn:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein Ring A,Ring B, R¹, R², and R³ are as defined and described in US 2017/0369476,the entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-oooo:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein R¹, R²,R³, and R⁴ are as defined and described in WO 2017/207385, the entiretyof which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-pppp:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein Ring A,X, Y, L¹, Cy¹, Cy², R¹ R⁸, R⁹, k, m, and n are as defined and describedin WO 2017/205766, the entirety of which is herein incorporated byreference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-qqqq:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein Ring A,L¹, Cy¹, Cy², R¹ R⁸, R⁹, m, and n are as defined and described in WO2017/205762, the entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof; thereby forming a compound of formula I-rrrr:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein Ring A,R¹, R³, R⁴, R⁵, and R¹⁶ are as defined and described in WO 2017/108723,the entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK1 and/or IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-ssss:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein Ring X,Z, R¹, R², R³, R⁴, R^(a) and p are as defined and described in WO2017/049068, the entirety of which is herein incorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-ssss:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein X, X′, Y,Y′, Z, R¹, R², R³, R^(4a), R^(4b), R^(5a), R^(5b) and R⁶ are as definedand described in WO 2017/033093, the entirety of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein IRAK is an IRAK4 binding moiety

or derivative thereof;thereby forming a compound of formula I-ssss:

or a pharmaceutically acceptable salt thereof, wherein L and IRAK are asdefined above and described in embodiments herein, and wherein X, X′, Y,Y′, Z, R¹, R², R³, R^(4a), R^(4b), R^(5a), R^(5b) and R⁶ are as definedand described in WO 2017/033093, the entirety of which is hereinincorporated by reference.

In certain embodiments, the present invention provides a compound offormula I, wherein LBM is a RNF114 binding moiety

or derivatives thereof;thereby forming a compound of formula I-iiii:

or derivative thereof, or a pharmaceutically acceptable salt thereof, asdescribed and defined in Ward, C. C., et al., bioRxiv (doi:https://doi.org/10.1101/439125), the entirety of each of which is hereinincorporated by reference.

Exemplary compounds of the invention are set forth in Table 1, below.

TABLE 1 Exemplary Compounds I-# Structure I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

I-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-683

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

I-305

I-306

I-307

I-308

I-309

I-310

I-311

I-312

I-313

I-314

I-315

I-316

I-317

I-318

I-319

I-320

I-321

I-322

I-323

I-324

I-325

I-326

I-327

I-328

I-329

I-330

I-331

I-332

I-333

I-334

I-335

I-336

I-337

I-338

I-339

I-340

I-341

I-342

I-343

I-344

I-345

I-346

I-347

I-348

I-349

I-350

I-351

I-352

I-353

I-354

I-355

I-356

I-357

I-358

I-359

I-360

I-361

I-362

I-363

I-364

I-365

I-366

I-367

I-368

I-369

I-370

I-371

I-372

I-373

I-374

I-375

I-376

I-377

I-378

I-379

I-380

I-381

I-382

I-383

I-384

I-385

I-386

I-387

I-388

I-389

I-390

I-391

I-392

I-393

I-394

I-395

I-396

I-397

I-398

I-399

I-400

I-401

I-402

I-403

I-404

I-405

I-406

I-407

I-408

I-409

I-410

I-411 +GET,1478 I-412

I-413

I-414

I-415

I-416

I-417

I-418

I-419

I-420

I-421

I-422

I-423

I-424

I-425

I-426

I-427

I-428

I-429

I-432

I-434

I-435

I-436

I-437

I-438

I-439

I-440

I-441

I-442

I-438

I-439

I-440

I-441

I-442

I-448

I-449

I-455

I-456

I-457

I-458

I-459

I-460

I-461

I-462

I-463

I-464

I-465

I-466

I-467

I-468

I-469

I-470

I-471

I-472

I-473

I-475

I-476

I-477

I-478

I-479

I-481

I-482

I-483

I-484

I-485

I-487

I-488

I-489

I-490

I-491

I-494

I-495

I-504

I-506

I-508

I-509

I-513

I-514

I-515

I-517

I-522

I-523

I-524

I-525

I-526

I-527

I-528

I-529

I-530

I-531

I-532

I-533

I-534

I-535

I-536

I-537

I-538

I-539

I-540

I-541

I-542

I-543

I-544

I-545

I-548

I-549

I-550

I-551

I-552

I-553

I-554

I-555

I-556

I-557

I-558

I-559

I-560

I-563

I-564

I-567

I-568

I-572

I-573

I-574

I-575

I-576

I-578

I-579

I-580

I-581

I-582

I-583

I-584

I-585

I-587

I-588

I-589

I-590

I-591

I-592

I-593

I-595

I-596

I-597

I-598

I-599

I-614

I-617

I-691

I-692

I-693

I-694

I-684

I-685

I-699

I-700

I-688

I-689

I-690

I-519

I-520

I-521

I-680

I-681

I-682

I-210

In some embodiments, the present invention provides a compound set forthin Table 1, above, or a pharmaceutically acceptable salt thereof.

4. General Methods of Providing the Present Compounds

The compounds of this invention may be prepared or isolated in generalby synthetic and/or semi-synthetic methods known to those skilled in theart for analogous compounds and by methods described in detail in theExamples, herein.

In the Schemes below, where a particular protecting group, leavinggroup, or transformation condition is depicted, one of ordinary skill inthe art will appreciate that other protecting groups, leaving groups,and transformation conditions are also suitable and are contemplated.Such groups and transformations are described in detail in March'sAdvanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B.Smith and J. March, 5^(th) Edition, John Wiley & Sons, 2001,Comprehensive Organic Transformations, R. C. Larock, 2^(nd) Edition,John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999,the entirety of each of which is hereby incorporated herein byreference.

As used herein, the phrase “oxygen protecting group” includes, forexample, carbonyl protecting groups, hydroxyl protecting groups, etc.Hydroxyl protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference. Examples ofsuitable hydroxyl protecting groups include, but are not limited to,esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkylethers, and alkoxyalkyl ethers. Examples of such esters includeformates, acetates, carbonates, and sulfonates. Specific examplesinclude formate, benzoyl formate, chloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate,pivaloate (trimethylacetyl), crotonate, 4-methoxy-crotonate, benzoate,p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl,9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples ofsuch silyl ethers include trimethylsilyl, triethylsilyl,t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and othertrialkylsilyl ethers. Alkyl ethers include methyl, benzyl,p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, andallyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers includeacetals such as methoxymethyl, methylthiomethyl,(2-methoxyethoxy)methyl, benzyloxymethyl,beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers.Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM),3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

Amino protecting groups are well known in the art and include thosedescribed in detail in Protecting Groups in Organic Synthesis, T. W.Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley & Sons, 1999, theentirety of which is incorporated herein by reference. Suitable aminoprotecting groups include, but are not limited to, aralkylamines,carbamates, cyclic imides, allyl amines, amides, and the like. Examplesof such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl,methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc),benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn),fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl,and the like.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 1 set forth below:

As depicted in Scheme 1, above, amine A-1 is coupled to acid A-2 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of formula I with a linker comprising an amide bond. Thesquiggly bond,

represents the portion of the linker between IRAK and the terminal aminogroup of A-1 or the portion of the linker between LBM and the terminalcarboxyl group of A-2, respectively. Additionally, an amide bond can beformed using coupling reagents known in the art such as, but not limitedto DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P,TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 2 set forth below:

As depicted in Scheme 2, above, amine A-1 is coupled to acid A-2 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of formula I with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between IRAK and the terminalamino group of A-1 or the portion of the linker between LBM and theterminal carboxyl group of A-2, respectively. Additionally, an amidebond can be formed using coupling reagents known in the art such as, butnot limited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl,DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 3 set forth below:

As depicted in Scheme 3, above, acid A-3 is coupled to amine A-4 usingthe coupling agent HATU in the presence of the base DIPEA in DMF to forma compound of formula I with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between IRAK and the terminalcarboxyl group of A-3 or the portion of the linker between LBM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 4 set forth below:

As depicted in Scheme 4, above, acid A-3 is coupled to amine A-4 usingthe coupling agent PyBOP in the presence of the base DIPEA in DMF toform a compound of formula I with a linker comprising an amide bond. Thesquiggly bond,

, represents the portion of the linker between IRAK and the terminalcarboxyl group of A-3 or the portion of the linker between LBM and theterminal amino group of A-4, respectively. Additionally, an amide bondcan be formed using coupling reagents known in the art such as, but notlimited to DCC, DIC, EDC, HBTU, HCTU, PyAOP, PyBrOP, BOP, BOP-Cl, DEPBT,T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 5 set forth below:

As depicted in Scheme 5, above, an S_(N)Ar displacement of fluoride A-6by amine A-5 is effected in the presence of the base DIPEA in DMF toform a compound of formula I with a linker comprising a secondary amine.The squiggly bond,

, represents the portion of the linker between IRAK and the terminalamino group of A-5.

In certain embodiments, compounds of the present invention are generallyprepared according to Scheme 6 set forth below:

As depicted in Scheme 6, above, an S_(N)Ar displacement of fluoride A-7by amine A-8 is effected in the presence of the base DIPEA in DMF toform a compound of formula I with a linker comprising a secondary amine.The squiggly bond,

, represents the portion of the linker between LBM and the terminalamino group of A-8.

As depicted in Scheme 7, above, reductive amination of the mixture ofaldehyde A-9 and amine A-10 is effected in the presence of NaHB(OAc)₃and KOAc in DMF/THF to form a compound of formula I with a linkercomprising a secondary amine. The squiggly bond,

, represents the portion of the linker between LBM and the terminalamino group of A-8.

One of skill in the art will appreciate that various functional groupspresent in compounds of the invention such as aliphatic groups,alcohols, carboxylic acids, esters, amides, aldehydes, halogens andnitriles can be interconverted by techniques well known in the artincluding, but not limited to reduction, oxidation, esterification,hydrolysis, partial oxidation, partial reduction, halogenation,dehydration, partial hydration, and hydration. “March's Advanced OrganicChemistry”, 5′ Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons,New York: 2001, the entirety of which is incorporated herein byreference. Such interconversions may require one or more of theaforementioned techniques, and certain methods for synthesizingcompounds of the invention are described below in the Exemplification.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. The amount of compound in compositions of this invention issuch that is effective to measurably degrade and/or inhibit an IRAKprotein kinase, or a mutant thereof, in a biological sample or in apatient. In certain embodiments, the amount of compound in compositionsof this invention is such that is effective to measurably degrade and/orinhibit an IRAK protein kinase, or a mutant thereof, in a biologicalsample or in a patient. In certain embodiments, a composition of thisinvention is formulated for administration to a patient in need of suchcomposition. In some embodiments, a composition of this invention isformulated for oral administration to a patient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

The term “pharmaceutically acceptable carrier, adjuvant, or vehicle”refers to a non-toxic carrier, adjuvant, or vehicle that does notdestroy the pharmacological activity of the compound with which it isformulated. Pharmaceutically acceptable carriers, adjuvants or vehiclesthat may be used in the compositions of this invention include, but arenot limited to, ion exchangers, alumina, aluminum stearate, lecithin,serum proteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

A “pharmaceutically acceptable derivative” means any non-toxic salt,ester, salt of an ester or other derivative of a compound of thisinvention that, upon administration to a recipient, is capable ofproviding, either directly or indirectly, a compound of this inventionor an inhibitorily or degratorily active metabolite or residue thereof.

As used herein, the term “inhibitorily active metabolite or residuethereof” means that a metabolite or residue thereof is also an inhibitorof an IRAK protein kinase, or a mutant thereof.

As used herein, the term “degratorily active metabolite or residuethereof” means that a metabolite or residue thereof is also a degraderof an IRAK protein kinase, or a mutant thereof.

Compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

Pharmaceutically acceptable compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, provided pharmaceutically acceptablecompositions may be formulated in a suitable ointment containing theactive component suspended or dissolved in one or more carriers.Carriers for topical administration of compounds of this inventioninclude, but are not limited to, mineral oil, liquid petrolatum, whitepetrolatum, propylene glycol, polyoxyethylene, polyoxypropylenecompound, emulsifying wax and water. Alternatively, providedpharmaceutically acceptable compositions can be formulated in a suitablelotion or cream containing the active components suspended or dissolvedin one or more pharmaceutically acceptable carriers. Suitable carriersinclude, but are not limited to, mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions in isotonic, pH adjustedsterile saline, or, preferably, as solutions in isotonic, pH adjustedsterile saline, either with or without a preservative such asbenzylalkonium chloride. Alternatively, for ophthalmic uses, thepharmaceutically acceptable compositions may be formulated in anointment such as petrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, pharmaceutically acceptable compositions of thisinvention are formulated for oral administration. Such formulations maybe administered with or without food. In some embodiments,pharmaceutically acceptable compositions of this invention areadministered without food. In other embodiments, pharmaceuticallyacceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that may be combinedwith the carrier materials to produce a composition in a single dosageform will vary depending upon the host treated, the particular mode ofadministration. Preferably, provided compositions should be formulatedso that a dosage of between 0.01-100 mg/kg body weight/day of thecompound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease being treated. Theamount of a compound of the present invention in the composition willalso depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

Compounds and compositions described herein are generally useful for thedegradation and/or inhibition of kinase activity of one or more enzymes.

Examples of kinases that are degraded and/or inhibited by the compoundsand compositions described herein and against which the methodsdescribed herein are useful include those of the interleukin-1receptor-associated kinase (IRAK) family of kinases, the members ofwhich include IRAK-1, IRAK-2, and IRAK-4, or a mutant thereof. Li etal., “IRAK-4: A novel member of the IRAK family with the properties ofan IRAK-kinase,” PNAS2002, 99(8), 5567-5572, Flannery et al., “Theinterleukin-1 receptor-associated kinases: Critical regulators of innateimmune signaling” Biochem Pharm 2010, 80(12), 1981-1991 incorporated byreference in its entirety.

The activity of a compound utilized in this invention as a degraderand/or inhibitor of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof,may be assayed in vitro, in vivo or in a cell line. In vitro assaysinclude assays that determine inhibition of either the phosphorylationactivity and/or the subsequent functional consequences, or ATPaseactivity of activated IRAK-1, IRAK-2, and/or IRAK-4, or a mutantthereof. Alternate in vitro assays quantitate the ability of theinhibitor to bind to IRAK-1, IRAK-2 and/or IRAK-4. Inhibitor binding maybe measured by radiolabeling the inhibitor prior to binding, isolatingthe inhibitor/IRAK-1, inhibitor/IRAK-2, or inhibitor/IRAK-4 complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment where newinhibitors are incubated with IRAK-1, IRAK-2, and/or IRAK-4 bound toknown radioligands. Representative in vitro and in vivo assays useful inassaying an IRAK-4 inhibitor include those described and disclosed in,e.g., Kim et al., “A critical role for IRAK4 kinase activity inToll-like receptor-mediated innate immunity,” J. Exp. Med. 2007 204(5),1025-1036; Lebakken et al., “A Fluorescence Lifetime Based Binding Assayto Characterize Kinase Inhibitors,” J. Biomol. Screen. 2007, 12(6),828-841; Maschera et al., “Overexpression of an enzymatically inactiveinterleukin-1-receptor-associated kinase activates nuclear factor-κB,”Biochem. J. 1999, 339, 227-231; Song et al., “The kinase activities ofinterleukin-e receptor associated kinase (IRAK)-1 and 4 are redundant inthe control of inflammatory cytokine expression in human cells,” Mol.Immunol. 2009, 46, 1458-1466, each of, the entirety of each of which isherein incorporated by reference. Detailed conditions for assaying acompound utilized in this invention as a degrader and/or inhibitor ofIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, are set forth in theExamples below.

The best characterized member of the IRAK family is the serine/threoninekinase IRAK-4. IRAK-4 is implicated in signaling innate immune responsesfrom Toll-like receptors (TLRs) and Toll/IL-1 receptors (TIRs).

Innate immunity detects pathogens through the recognition ofpathogen-associated molecular patterns by TLRs, when then links to theadaptive immune response. TLRs recognize conserved structures of bothmicrobes and endogenous molecules. TLRs which recognize bacterial andfungal components are located on the cell surface, whereas TLRs whichrecognize viral or microbial nucleic acids are localized tointracellular membranes such as endosomes and phagosomes. Cell surfaceTLRs can be targeted by small molecules and antibodies, whereasintracellular TLRs require targeting with oligonucleotides.

TLRs mediate the innate immune response by upregulating the expressionof inflammatory genes in multiple target cells. See, e.g., Sen et al.,“Transcriptional signaling by double-stranded RNA: role of TLR3,”Cytokine & Growth Factor Rev. 2005, 16, 1-14, incorporated by referencein its entirety. While TLR-mediated inflammatory response is criticalfor innate immunity and host defense against infections, uncontrolledinflammation is detrimental to the host leading to sepsis and chronicinflammatory diseases, such as chronic arthritis, atherosclerosis,multiple sclerosis, cancers, autoimmune disorders such as rheumatoidarthritis, lupus, asthma, psoriasis, and inflammatory bowel diseases.

Upon binding of a ligand, most TLRs recruit the adaptor molecule MyD88through the TIR domain, mediating the MyD88-dependent pathway. MyD88then recruits IRAK-4, which engages with the nuclear factor-κB (NF-κB),mitogen-activated protein (MAP) kinase and interferon-regulatory factorcascades and leads to the induction of pro-inflammatory cytokines. Theactivation of NF-κB results in the induction of inflammatory cytokinesand chemokines, such as TNF-α, IL-1 α, IL-6 and IL-8. The kinaseactivity of IRAK-4 has been shown to play a critical role in theTLR-mediated immune and inflammatory responses. IRAK4 is a key mediatorof the innate immune response orchestrated by interleukin-1 receptor(IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), andToll-like receptors (TLRs). Inactivation of IRAK-1 and/or IRAK-4activity has been shown to result in diminished production of cytokinesand chemokines in response to stimulation of IL-1 and TLR ligands. See,e.g., Picard et al., “Clinical features and outcome of patients withIRAK-4 and MyD88 deficiency,” Medicine (Baltimore), 2010, 89(6), 043-25;Li, “IRAK4 in TLR/IL-1R signaling: Possible clinical applications,” EurJ. Immunology 2008, 38:614-618; Cohen et al., “Targeting protein kinasesfor the development of anti-inflammatory drugs,” Curr Opin. Cell Bio.2009, 21:317-324; Flannery et al., “The interleukin-1receptor-associated kinases: Critical regulators of innate immunesignalling,” Biochem. Pharm. 2010, 80(12), 1981-1991; Gottipati et al.,“IRAK1: A critical signaling mediator of innate immunity,” CellularSignaling 2008, 20, 269-276; Kim et al., “A critical role for IRAK4kinase activity in Toll-like receptor-mediated innate immunity,” J. Exp.Med. 2007 204(5), 1025-1036; Koziczak-Holbro et al., “IRAK-4 KinaseActivity Is Required for Interleukin-1 (IL-1) Receptor- and Toll-likeReceptor 7-mediated Signaling and Gene Expression,” J. Biol. Chem. 2007,282(18), 13552-13560; Kubo-Murai et al., “IRAK-4-dependent Degradationof IRAK-1 is a Negative Feedback Signal for TLR-mediated NF-κBActivation,” J. Biochem. 2008, 143, 295-302; Maschera et al.,“Overexpression of an enzymatically inactiveinterleukin-1-receptor-associated kinase activates nuclear factor-κB,”Biochem. J. 1999, 339, 227-231; Lin et al., “Helical assembly in theMyD88-IRAK4-IRAK2 complex in TLR/IL-1R signalling,” Nature 2010,465(17), 885-891; Suzuki et al., “IRAK-4 as the central TIR signalingmediator in innate immunity,” TRENDS in Immunol. 2002, 23(10), 503-506;Suzuki et al., “Severe impairment of interleukin-1 and Toll-likereceptor signalling in mice lacking IRAK-4,” Nature 2002, 416, 750-754;Swantek et al., “IL-1 Receptor-Associated Kinase Modulates HostResponsiveness to Endotoxin,” J. Immunol. 2000, 164, 4301-4306;Hennessy, E., et al., “Targeting Toll-like receptors: emergingtherapeutics?” Nature Reviews, vol. 9, pp: 293-307 (2010); Dinarello, C.“Interleukin-18 and the Pathogenesis of Inflammatory Diseases,” Seminarsin Nephrology, vol. 27, no. 1, pp: 98-114 (2007), each of, the entiretyof each of which is herein incorporated by reference. In fact, knockdownmice that express a catalytically inactive mutant IRAK-4 protein arecompletely resistant to septic shock and show impaired IL-1 activity.Moreover, these mice are resistant to joint and boneinflammation/destruction in an arthritis model, suggesting that IRAK-4may be targeted to treat chronic inflammation. Further, while IRAK-4appears to be vital for childhood immunity against some pyogenicbacteria, it has been shown to play a redundant role in protectiveimmunity to most infections in adults, as demonstrated by one study inwhich patients older than 14 lacking IRAK-4 activity exhibited noinvasive infections. Cohen et al., “Targeting protein kinases for thedevelopment of anti-inflammatory drugs,” Curr. Opin. Cell Bio. 2009,21:317-324; Ku et al., “Selective predisposition to bacterial infectionsin IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwiseredundant in protective immunity,” J. Exp. Med. 2007, 204(10),2407-2422; Picard et al., “Inherited human IRAK-4 deficiency: anupdate,” Immunol. Res. 2007, 38, 347-352; Song et al., “The kinaseactivities of interleukin-e receptor associated kinase (IRAK)-1 and 4are redundant in the control of inflammatory cytokine expression inhuman cells,” Mol. Immunol. 2009, 46, 1458-1466; Rokosz, L. et al.,“Kinase inhibitors as drugs for chronic inflammatory and immunologicaldiseases: progress and challenges,” Expert Opinions on TherapeuticTargets, 12(7), pp: 883-903 (2008); Gearing, A. “Targeting toll-likereceptors for drug development: a summary of commercial approaches,”Immunology and Cell Biology, 85, pp: 490-494 (2007); Dinarello, C.“IL-1: Discoveries, controversies and future directions,” EuropeanJournal of Immunology, 40, pp: 595-653 (2010), each of, the entirety ofeach of which is herein incorporated by reference. Because TLRactivation triggers IRAK-4 kinase activity, IRAK-4 inhibition presentsan attractive target for treating the underlying causes of inflammationin countless diseases.

Representative IRAK-4 inhibitors include those described and disclosedin e.g., Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3211-3214;Buckley et al., Bioorg. Med. Chem. Lett. 2008, 18, 3291-3295; Buckley etal., Bioorg. Med. Chem. Lett. 2008, 18, 3656-3660; Powers et al.,“Discovery and initial SAR of inhibitors of interleukin-1receptor-associated kinase-4,” Bioorg. Med. Chem. Lett. 2006, 16,2842-2845; Wng et al., “IRAK-4 Inhibitors for Inflammation,” Curr Topicsin Med. Chem. 2009, 9, 724-737, each of, the entirety of each of whichis herein incorporated by reference.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a disease or disorder, or one or more symptoms thereof, asdescribed herein. In some embodiments, treatment may be administeredafter one or more symptoms have developed. In other embodiments,treatment may be administered in the absence of symptoms. For example,treatment may be administered to a susceptible individual prior to theonset of symptoms (e.g., in light of a history of symptoms and/or inlight of genetic or other susceptibility factors). Treatment may also becontinued after symptoms have resolved, for example to prevent or delaytheir recurrence.

Provided compounds are degraders and/or inhibitors of one of more ofIRAK-1, IRAK-2, and/or IRAK-4 and are therefore useful for treating oneor more disorders associated with activity of one or more of IRAK-1,IRAK-2, and/or IRAK-4. Thus, in certain embodiments, the presentinvention provides a method for treating a IRAK-1-mediated, aIRAK-2-mediated, and/or a IRAK-4-mediated disorder comprising the stepof administering to a patient in need thereof a compound of the presentinvention, or pharmaceutically acceptable composition thereof.

As used herein, the terms “IRAK-1-mediated”, “IRAK-2-mediated”, and/or“IRAK-4-mediated” disorders, diseases, and/or conditions as used hereinmeans any disease or other deleterious condition in which one or more ofIRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, are known to play arole. Accordingly, another embodiment of the present invention relatesto treating or lessening the severity of one or more diseases in whichone or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, areknown to play a role.

In some embodiments, the present invention provides a method fortreating one or more disorders, diseases, and/or conditions wherein thedisorder, disease, or condition is a cancer, a neurodegenative disorder,a viral disease, an autoimmune disease, an inflammatory disorder, ahereditary disorder, a hormone-related disease, a metabolic disorder,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, liver disease, pathologic immuneconditions involving T cell activation, a cardiovascular disorder, or aCNS disorder.

Diseases and conditions treatable according to the methods of thisinvention include, but are not limited to, cancer (see, e.g., Ngo, V. etal., “Oncogenically active MYD88 mutations in human lymphoma,” Nature,vol. 000, pp: 1-7 (2010); Lust, J. et al., “Induction of a ChronicDisease State in patients With Smoldering of Indolent Multiple Myelomaby Targeting Interleukin 1β-Induced Interleukin 6 Production and theMyeloma Proliferative Component,” Mayo Clinic Proceedings, 84(2), pp:114-122 (2009)), diabetes, cardiovascular disease, viral disease,autoimmune diseases such as lupus (see, e.g., Dinarello, C.“Interleukin-18 and the Pathogenesis of Inflammatory Diseases,” Seminarsin Nephrology, vol. 27, no. 1, pp: 98-114 (2007); Cohen et al.,“Targeting protein kinases for the development of anti-inflammatorydrugs,” Curr Opin. Cell Bio. 2009, 21:317-324) and rheumatoid arthritis(see, e.g., Geyer, M. et al., “Actual status of antiinterleukin-1therapies in rheumatic diseases,” Current Opinion in Rheumatology, 22,pp: 246-251 (2010)), autoinflammatory syndromes (see, e.g., Hoffman, H.et al., “Efficacy and Safety of Rilonacept (Interleukin-1 Trap) inPatients with Cryopyrin-Associated Periodic Syndromes,” Arthritis &Rheumatism, vol. 58, no. 8, pp: 2443-2452 (2008)), atherosclerosis,psoriasis, allergic disorders, inflammatory bowel disease (see, e.g.,Cario, E. “Therapeutic Impact of Toll-like Receptors on InflammatoryBowel Diseases: A Multiple-edged Sword,” Inflamm. Bowel Dis., 14, pp:411-421 (2008)), inflammation (see, e.g., Dinarello, C. “Interleukin 1and interleukin 18 as mediators of inflammation and the aging process,”The American Journal of Clinical Nutrition, 83, pp: 447S-455S (2006)),acute and chronic gout and gouty arthritis (see, e.g., Terkeltaub, R.“Update on gout: new therapeutic strategies and options,” Nature, vol.6, pp: 30-38 (2010); Weaver, A. “Epidemiology of gout,” Cleveland ClinicJournal of Medicine, vol. 75, suppl. 5, pp: S9-S12 (2008); Dalbeth, N.et al., “Hyperuricaemia and gout: state of the art and futureperspectives,” Annals of Rheumatic Diseases, 69, pp: 1738-1743 (2010);Martinon, F. et al., “Gout-associated uric acid crystals activate theNALP3 inflammasome,” Nature, vol. 440, pp: 237-241 (2006); So, A. etal., “A pilot study of IL-1 inhibition by anakinra in acute gout,”Arthritis Research & Therapy, vol. 9, no. 2, pp: 1-6 (2007); Terkeltaub,R. et al., “The interleukin 1 inhibitor rilonacept in treatment ofchronic gouty arthritis: results of a placebo-controlled, monosequencecrossover, non-randomised, single-blind pilot study,” Annals ofRheumatic Diseases, 68, pp: 1613-1617 (2009); Torres, R. et al.,“Hyperalgesia, synovitis and multiple biomarkers of inflammation aresuppressed by interleukin 1 inhibition in a novel animal model of goutyarthritis,” Annals of Rheumatic Diseases, 68, pp: 1602-1608 (2009)),neurological disorders, metabolic syndrome (see, e.g., Troseid, M. “Therole of interleukin-18 in the metabolic syndrome,” CardiovascularDiabetology, 9:11, pp:1-8 (2010)), immunodeficiency disorders such asAIDS and HIV (see, e.g., Iannello, A. et al., “Role of Interleukin-18 inthe Development and Pathogenesis of AIDS,” AIDS Reviews, 11, pp: 115-125(2009)), destructive bone disorders (see, e.g., Hennessy, E., et al.,“Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews,vol. 9, pp: 293-307 (2010)), osteoarthritis, proliferative disorders,Waldenström's Macroglobulinemia (see, e.g., Treon, et al., “Whole genomesequencing reveals a widely expressed mutation (MYD88 L265P) withoncogenic activity in Waldenström's Macroglobulinemia” 53^(rd) ASHAnnual Meeting; Xu, et al., “A somatic variant in MYD88 (L256P) revealedby whole genome sequencing differentiates lymphoplasmacytic lymphomafrom marginal zone lymphomas” 53^(rd) ASH Annual Meeting; Yang et al.,“Disruption of MYD88 pathway signaling leads to loss of constitutiveIRAK1, NK-kB and JAK/STAT signaling and induces apoptosis of cellsexpressing the MYD88 L265P mutation in Waldenström's Macroglobulinemia”53^(rd) ASH Annual Meeting; Iriyama et al., “Clinical significance ofgenetic mutations of CD79B, CARD11, MYD88, and EZH2 genes in diffuselarge B-cell lymphoma patients” 53^(rd) ASH Annual Meeting; infectiousdiseases, conditions associated with cell death, pathologic immuneconditions involving T cell activation, and CNS disorders in a patient.In one embodiment, a human patient is treated with a compound of thecurrent invention and a pharmaceutically acceptable carrier, adjuvant,or vehicle, wherein said compound is present in an amount to measurablydegrade and/or inhibit IRAK-1 only, IRAK-2-only, IRAK-4-only and/orIRAK1 and IRAK4 kinase activity.

Compounds of the current invention are useful in the treatment of aproliferative disease selected from a benign or malignant tumor, solidtumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder,breast, stomach, gastric tumors, ovaries, colon, rectum, prostate,pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma, gastrointestinal cancer, especially colon carcinoma orcolorectal adenoma, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, Hodgkins and Non-Hodgkins, amammary carcinoma, follicular carcinoma, undifferentiated carcinoma,papillary carcinoma, seminoma, melanoma, an IL-1 driven disorder, anMyD88 driven disorder, Smoldering of indolent multiple myeloma, orhematological malignancies (including leukemia, diffuse large B-celllymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chroniclymphocytic lymphoma, primary effusion lymphoma, Burkittlymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia(WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,intravascular large B-cell lymphoma).

In some embodiments the proliferative disease which can be treatedaccording to the methods of this invention is an MyD88 driven disorder.In some embodiments, the MyD88 driven disorder which can be treatedaccording to the methods of this invention is selected from ABC DLBCL,Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneousT-cell lymphoma and chronic lymphocytic leukemia.

In some embodiments the proliferative disease which can be treatedaccording to the methods of this invention is an IL-1 driven disorder.In some embodiments the IL-1 driven disorder is Smoldering of indolentmultiple myeloma.

Compounds according to the invention are useful in the treatment ofinflammatory or obstructive airways diseases, resulting, for example, inreduction of tissue damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression. Inflammatory orobstructive airways diseases to which the present invention isapplicable include asthma of whatever type or genesis including bothintrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mildasthma, moderate asthma, severe asthma, bronchitic asthma,exercise-induced asthma, occupational asthma and asthma inducedfollowing bacterial infection. Treatment of asthma is also to beunderstood as embracing treatment of subjects, e.g. of less than 4 or 5years of age, exhibiting wheezing symptoms and diagnosed or diagnosableas “wheezy infants”, an established patient category of major medicalconcern and now often identified as incipient or early-phase asthmatics.

Compounds according to the invention are useful in the treatment ofheteroimmune diseases. Examples of such heteroimmune diseases include,but are not limited to, graft versus host disease, transplantation,transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens,latex, drugs, foods, insect poisons, animal hair, animal dander, dustmites, or cockroach calyx), type I hypersensitivity, allergicconjunctivitis, allergic rhinitis, and atopic dermatitis.

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, such as therapy for orintended to restrict or abort symptomatic attack when it occurs, forexample antiinflammatory or bronchodilatory. Prophylactic benefit inasthma may in particular be apparent in subjects prone to “morningdipping”. “Morning dipping” is a recognized asthmatic syndrome, commonto a substantial percentage of asthmatics and characterised by asthmaattack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant form any previously administeredsymptomatic asthma therapy.

Compounds of the current invention can be used for other inflammatory orobstructive airways diseases and conditions to which the presentinvention is applicable and include acute lung injury (ALI), adult/acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonary,airways or lung disease (COPD, COAD or COLD), including chronicbronchitis or dyspnea associated therewith, emphysema, as well asexacerbation of airways hyperreactivity consequent to other drugtherapy, in particular other inhaled drug therapy. The invention is alsoapplicable to the treatment of bronchitis of whatever type or genesisincluding, but not limited to, acute, arachidic, catarrhal, croupus,chronic or phthinoid bronchitis. Further inflammatory or obstructiveairways diseases to which the present invention is applicable includepneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

With regard to their anti-inflammatory activity, in particular inrelation to inhibition of eosinophil activation, compounds of theinvention are also useful in the treatment of eosinophil relateddisorders, e.g. eosinophilia, in particular eosinophil related disordersof the airways (e.g. involving morbid eosinophilic infiltration ofpulmonary tissues) including hypereosinophilia as it effects the airwaysand/or lungs as well as, for example, eosinophil-related disorders ofthe airways consequential or concomitant to Loffler's syndrome,eosinophilic pneumonia, parasitic (in particular metazoan) infestation(including tropical eosinophilia), bronchopulmonary aspergillosis,polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilicgranuloma and eosinophil-related disorders affecting the airwaysoccasioned by drug-reaction.

Compounds of the invention are also useful in the treatment ofinflammatory or allergic conditions of the skin, for example psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, systemic lupus erythematosus, pemphigus vulgaris,pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosaacquisita, acne vulgaris, and other inflammatory or allergic conditionsof the skin.

Compounds of the invention may also be used for the treatment of otherdiseases or conditions, such as diseases or conditions having aninflammatory component, for example, treatment of diseases andconditions of the eye such as ocular allergy, conjunctivitis,keratoconjunctivitis sicca, and vernal conjunctivitis, diseasesaffecting the nose including allergic rhinitis, and inflammatory diseasein which autoimmune reactions are implicated or having an autoimmunecomponent or etiology, including autoimmune hematological disorders(e.g. hemolytic anemia, aplastic anemia, pure red cell anemia andidiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoidarthritis, polychondritis, scleroderma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis,Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory boweldisease (e.g. ulcerative colitis and Crohn's disease), irritable bowelsyndrome, celiac disease, periodontitis, hyaline membrane disease,kidney disease, glomerular disease, alcoholic liver disease, multiplesclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis,interstitial lung fibrosis, psoriatic arthritis, systemic juvenileidiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis,vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis(with and without nephrotic syndrome, e.g. including idiopathicnephrotic syndrome or minal change nephropathy), chronic granulomatousdisease, endometriosis, leptospiriosis renal disease, glaucoma, retinaldisease, ageing, headache, pain, complex regional pain syndrome, cardiachypertrophy, musclewasting, catabolic disorders, obesity, fetal growthretardation, hyperchlolesterolemia, heart disease, chronic heartfailure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma (allergic and non-allergic, mild,moderate, severe, bronchitic, and exercise-induced), acute lung injury,acute respiratory distress syndrome, eosinophilia, hypersensitivities,anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases,COPD (reduction of damage, airways inflammation, bronchialhyperreactivity, remodeling or disease progression), pulmonary disease,cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, Type 1 diabetes, or Type2 diabetes, appendicitis, atopic dermatitis, asthma, allergy,blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis,cholangitis, cholecystitis, chronic graft rejection, colitis,conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis,dermatomyositis, encephalitis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis,hidradenitis suppurativa, immunoglobulin A nephropathy, interstitiallung disease, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is an disease of the skin. Insome embodiments, the inflammatory disease of the skin is selected fromcontact dermatitits, atompic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigusvulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysisbullosa acquisita, and other inflammatory or allergic conditions of theskin.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic jubenileidiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome(CAPS), and osteoarthritis.

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is a TH17 mediated disease.In some embodiments the TH17 mediated disease is selected from Systemiclupus erythematosus, Multiple sclerosis, and inflammatory bowel disease(including Crohn's disease or ulcerative colitis).

In some embodiments the inflammatory disease which can be treatedaccording to the methods of this invention is selected from Sjogren'ssyndrome, allergic disorders, osteoarthritis, conditions of the eye suchas ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernalconjunctivitis, and diseases affecting the nose such as allergicrhinitis.

Cardiovascular diseases which can be treated according to the methods ofthis invention include, but are not limited to, restenosis,cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke,congestive heart failure, angina pectoris, reocclusion afterangioplasty, restenosis after angioplasty, reocclusion afteraortocoronary bypass, restenosis after aortocoronary bypass, stroke,transitory ischemia, a peripheral arterial occlusive disorder, pulmonaryembolism, and deep venous thrombosis.

In some embodiments, the neurodegenerative disease which can be treatedaccording to the methods of this invention include, but are not limitedto, Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's disease, cerebral ischemia, andneurodegenerative disease caused by traumatic injury, glutamateneurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolicsyndrome, obesity, organ transplantation and graft versus host disease.

The loss of IRAK4 function results in decreased AR levels in an in vivomurine model of Alzheimer's disease and was associated with diminishedmicrogliosis and astrogliosis in aged mice. Analysis of microgliaisolated from the adult mouse brain revealed an altered pattern of geneexpression associated with changes in microglial phenotype that wereassociated with expression of IRF transcription factors that governmicroglial phenotype. Further, loss of IRAK4 function also promotedamyloid clearance mechanisms, including elevated expression ofinsulin-degrading enzyme. Finally, blocking IRAK function restoredolfactory behavior (Cameron et al. “Loss of InterleukinReceptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology andAlters Microglial Phenotype in a Mouse Model of Alzheimer's Disease”Journal of Neuroscience (2012) 32(43), 15112-15123.

In some embodiments the invention provides a method of treating,preventing or lessening the severity of Alzheimer's disease comprisingadministering to a patient in need thereof a compound of formula I or apharmaceutically acceptable salt or composition thereof.

In some embodiments the invention provides a method of treating adisease or condition commonly occurring in connection withtransplantation. In some embodiments, the disease or condition commonlyoccurring in connection with transplantation is selected from organtransplantation, organ transplant rejection, and graft versus hostdisease.

In some embodiments the invention provides a method of treating ametabolic disease. In some embodiments the metabolic disease is selectedfrom Type 1 diabetes, Type 2 diabetes, metabolic syndrome, and obesity.

In some embodiments the invention provides a method of treating a viraldisease. In some embodiments, the viral infection is HIV infection.

Furthermore, the invention provides the use of a compound according tothe definitions herein, or a pharmaceutically acceptable salt, or ahydrate or solvate thereof for the preparation of a medicament for thetreatment of a proliferative disease, an inflammatory disease, anobstructive respiratory disease, a cardiovascular disease, a metabolicdisease, a neurological disease, a neurodegenerative disease, a viraldisease, or a disorder commonly occurring in connection withtransplantation.

Combination Therapies

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents, which are normally administered to treatthat condition, may be administered in combination with compounds andcompositions of this invention. As used herein, additional therapeuticagents that are normally administered to treat a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated.”

In certain embodiments, a provided combination, or composition thereof,is administered in combination with another therapeutic agent.

In some embodiments, the present invention provides a method of treatinga disclosed disease or condition comprising administering to a patientin need thereof an effective amount of a compound disclosed herein or apharmaceutically acceptable salt thereof and co-administeringsimultaneously or sequentially an effective amount of one or moreadditional therapeutic agents, such as those described herein. In someembodiments, the method includes co-administering one additionaltherapeutic agent. In some embodiments, the method includesco-administering two additional therapeutic agents. In some embodiments,the combination of the disclosed compound and the additional therapeuticagent or agents acts synergistically.

Examples of agents the combinations of this invention may also becombined with include, without limitation: treatments for Alzheimer'sDisease such as Aricept® and Excelon®; treatments for HIV such asritonavir; treatments for Parkinson's Disease such as L-DOPA/carbidopa,entacapone, ropinrole, pramipexole, bromocriptine, pergolide,trihexephendyl, and amantadine; agents for treating Multiple Sclerosis(MS) such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, andmitoxantrone; treatments for asthma such as albuterol and Singulair®;agents for treating schizophrenia such as zyprexa, risperdal, seroquel,and haloperidol; anti-inflammatory agents such as corticosteroids, TNFblockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;immunomodulatory and immunosuppressive agents such as cyclosporin,tacrolimus, rapamycin, mycophenolate mofetil, interferons,corticosteroids, cyclophophamide, azathioprine, and sulfasalazine;neurotrophic factors such as acetylcholinesterase inhibitors, MAOinhibitors, interferons, anti-convulsants, ion channel blockers,riluzole, and anti-Parkinsonian agents; agents for treatingcardiovascular disease such as beta-blockers, ACE inhibitors, diuretics,nitrates, calcium channel blockers, and statins; agents for treatingliver disease such as corticosteroids, cholestyramine, interferons, andanti-viral agents; agents for treating blood disorders such ascorticosteroids, anti-leukemic agents, and growth factors; agents thatprolong or improve pharmacokinetics such as cytochrome P450 inhibitors(i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g.,ketokenozole and ritonavir), and agents for treating immunodeficiencydisorders such as gamma globulin.

In certain embodiments, combination therapies of the present invention,or a pharmaceutically acceptable composition thereof, are administeredin combination with a monoclonal antibody or an siRNA therapeutic.

Those additional agents may be administered separately from a providedcombination therapy, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a combination ofthe present invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

One or more other therapeutic agent may be administered separately froma compound or composition of the invention, as part of a multiple dosageregimen. Alternatively, one or more other therapeutic agents agents maybe part of a single dosage form, mixed together with a compound of thisinvention in a single composition. If administered as a multiple dosageregime, one or more other therapeutic agent and a compound orcomposition of the invention may be administered simultaneously,sequentially or within a period of time from one another, for examplewithin 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,18, 20, 21, 22, 23, or 24 hours from one another. In some embodiments,one or more other therapeutic agent and a compound or composition of theinvention are administered as a multiple dosage regimen within greaterthan 24 hours aparts.

In one embodiment, the present invention provides a compositioncomprising a compound of formula I and one or more additionaltherapeutic agents. The therapeutic agent may be administered togetherwith a compound of formula I, or may be administered prior to orfollowing administration of a compound of formula I. Suitabletherapeutic agents are described in further detail below. In certainembodiments, a compound of formula I may be administered up to 5minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4hours, 5, hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours,12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hoursbefore the therapeutic agent. In other embodiments, a compound offormula I may be administered up to 5 minutes, 10 minutes, 15 minutes,30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5, hours, 6 hours, 7hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14hours, 15 hours, 16 hours, 17 hours, or 18 hours following thetherapeutic agent.

In another embodiment, the present invention provides a method oftreating an inflammatory disease, disorder or condition by administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents. Such additional therapeutic agents may besmall molecules or recombinant biologic agents and include, for example,acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®),antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine(Aralen®), methotrexate (Rheumatrex®), gold salts such as goldthioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin(Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine(Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®),cyclosporine (Sandimmune®), leflunomide (Arava®) and “anti-TNF” agentssuch as etanercept (Enbrel®), infliximab (Remicade®), golimumab(Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®),“anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such astofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®), “anti-IL-6” agents such astocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc®or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot®, anticholinergics or antispasmodics such as dicyclomine(Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA,Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®),pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®),salmeterol xinafoate (Serevent®) and formoterol (Foradil®),anticholinergic agents such as ipratropium bromide (Atrovent®) andtiotropium (Spiriva®), inhaled corticosteroids such as beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), andflunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium(Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such asomalizumab (Xolair®), nucleoside reverse transcriptase inhibitors suchas zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine(Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine(Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®),lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine(Hivid®), non-nucleoside reverse transcriptase inhibitors such asdelavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®)and etravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), doxorubicin(Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), anddexamethasone (Decadron®) in combination with lenalidomide (Revlimid®),or any combination(s) thereof.

In another embodiment, the present invention provides a method oftreating gout comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, probenecid,allopurinol and febuxostat (Uloric®).

In another embodiment, the present invention provides a method oftreating rheumatoid arthritis comprising administering to a patient inneed thereof a compound of formula I and one or more additionaltherapeutic agents selected from non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, corticosteroids such as prednisone, prednisolone,methylprednisolone, hydrocortisone, and the like, sulfasalazine(Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) andchloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such asgold thioglucose (Solganal®), gold thiomalate (Myochrysine®) andauranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®),azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil(Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and“anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®),golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab(Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept(Arcalyst®), antibodies such as rituximab (Rituxan®), “anti-T-cell”agents such as abatacept (Orencia®) and “anti-IL-6” agents such astocilizumab (Actemra®).

In some embodiments, the present invention provides a method of treatingosteoarthritis comprising administering to a patient in need thereof acompound of formula I and one or more additional therapeutic agentsselected from acetaminophen, non-steroidal anti-inflammatory drugs(NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) andcelecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®)and monoclonal antibodies such as tanezumab.

In some embodiments, the present invention provides a method of treatinglupus comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromacetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such asaspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib,corticosteroids such as prednisone, prednisolone, methylprednisolone,hydrocortisone, and the like, antimalarials such as hydroxychloroquine(Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®),methotrexate (Rheumatrex®), azathioprine (Imuran®) and anticoagulantssuch as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

In some embodiments, the present invention provides a method of treatinginflammatory bowel disease comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from mesalamine (Asacol®) sulfasalazine (Azulfidine®),antidiarrheals such as diphenoxylate (Lomotil®) and loperamide(Imodium®), bile acid binding agents such as cholestyramine, alosetron(Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk ofMagnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® andSenokot® and anticholinergics or antispasmodics such as dicyclomine(Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagylor ciprofloxacin.

In some embodiments, the present invention provides a method of treatingasthma comprising administering to a patient in need thereof a compoundof formula I and one or more additional therapeutic agents selected fromSingulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterolacetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterolxinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agentssuch as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®),inhaled corticosteroids such as prednisone, prednisolone, beclomethasonedipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide(Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®),flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolynsodium (Intal®), methylxanthines such as theophylline (Theo-Dur®,Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgEantibodies such as omalizumab (Xolair®).

In some embodiments, the present invention provides a method of treatingCOPD comprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected frombeta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA),levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate(Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate(Serevent®) and formoterol (Foradil®), anticholinergic agents such asipratropium bromide (Atrovent®) and tiotropium (Spiriva®),methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®,Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such asprednisone, prednisolone, beclomethasone dipropionate (Beclovent®,Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone(Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®,Symbicort®, and Dulera®,

In some embodiments, the present invention provides a method of treatingHIV comprising administering to a patient in need thereof a compound offormula I and one or more additional therapeutic agents selected fromnucleoside reverse transcriptase inhibitors such as zidovudine(Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®),abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®),emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine(Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®),non-nucleoside reverse transcriptase inhibitors such as delavirdine(Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) andetravirine (Intelence®), nucleotide reverse transcriptase inhibitorssuch as tenofovir (Viread®), protease inhibitors such as amprenavir(Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®),fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir(Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir(Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitorssuch as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integraseinhibitors such as raltegravir (Isentress®), and combinations thereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, a SYK inhibitor, and combinations thereof.

In another embodiment, the present invention provides a method oftreating a solid tumor comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, ahedgehog signaling inhibitor, a BTK inhibitor, a JAK/pan-JAK inhibitor,a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinationsthereof.

In another embodiment, the present invention provides a method oftreating a hematological malignancy comprising administering to apatient in need thereof a compound of formula I and a Hedgehog (Hh)signaling pathway inhibitor. In some embodiments, the hematologicalmalignancy is DLBCL (Ramirez et al “Defining causative factorscontributing in the activation of hedgehog signaling in diffuse largeB-cell lymphoma” Leuk. Res. (2012), published online July 17, andincorporated herein by reference in its entirety).

In another embodiment, the present invention provides a method oftreating diffuse large B-cell lymphoma (DLBCL) comprising administeringto a patient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from rituximab (Rituxan®),cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®),vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, andcombinations thereof.

In another embodiment, the present invention provides a method oftreating multiple myeloma comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from bortezomib (Velcade®), and dexamethasone(Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, aJAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYKinhibitor in combination with lenalidomide (Revlimid®).

In another embodiment, the present invention provides a method oftreating Waldenström's macroglobulinemia comprising administering to apatient in need thereof a compound of formula I and one or moreadditional therapeutic agents selected from chlorambucil (Leukeran®),cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine(Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, aBTK inhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3Kinhibitor, and a SYK inhibitor.

In some embodiments, one or more other therapeutic agent is anantagonist of the hedgehog pathway. Approved hedgehog pathway inhibitorswhich may be used in the present invention include sonidegib (Odomzo®,Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both fortreatment of basal cell carcinoma.

In some embodiments, one or more other therapeutic agent is a Poly ADPribose polymerase (PARP) inhibitor. In some embodiments, a PARPinhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib(Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib(MDV3800/BMN 673/LT00673, Medivation/Pfizer/Biomarin); veliparib(ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

In some embodiments, one or more other therapeutic agent is a histonedeacetylase (HDAC) inhibitor. In some embodiments, an HDAC inhibitor isselected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®,Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®,Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals)(NCT00866333); and chidamide (Epidaza®, HBI-8000, ChipscreenBiosciences, China).

In some embodiments, one or more other therapeutic agent is a CDKinhibitor, such as a CDK4/CDK6 inhibitor. In some embodiments, a CDK 4/6inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib(Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); andtrilaciclib (G1T28, G1 Therapeutics).

In some embodiments, one or more other therapeutic agent is a folic acidinhibitor. Approved folic acid inhibitors useful in the presentinvention include pemetrexed (Alimta®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is a CCchemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studiedthat may be useful in the present invention include mogamulizumab(Poteligeo®, Kyowa Hakko Kirin, Japan).

In some embodiments, one or more other therapeutic agent is anisocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studiedwhich may be used in the present invention include AG120 (Celgene;NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032(Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agent is an arginaseinhibitor. Arginase inhibitors being studied which may be used in thepresent invention include AEB1102 (pegylated recombinant arginase,Aeglea Biotherapeutics), which is being studied in Phase 1 clinicaltrials for acute myeloid leukemia and myelodysplastic syndrome(NCT02732184) and solid tumors (NCT02561234); and CB-1158 (CalitheraBiosciences).

In some embodiments, one or more other therapeutic agent is aglutaminase inhibitor. Glutaminase inhibitors being studied which may beused in the present invention include CB-839 (Calithera Biosciences).

In some embodiments, one or more other therapeutic agent is an antibodythat binds to tumor antigens, that is, proteins expressed on the cellsurface of tumor cells. Approved antibodies that bind to tumor antigenswhich may be used in the present invention include rituximab (Rituxan®,Genentech/Biogenldec); ofatumumab (anti-CD20, Arzerra®,GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech),ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, SpectrumPharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech),dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics);trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumabemtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); andpertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin(anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

In some embodiments, one or more other therapeutic agent is atopoisomerase inhibitor. Approved topoisomerase inhibitors useful in thepresent invention include irinotecan (Onivyde®, MerrimackPharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomeraseinhibitors being studied which may be used in the present inventioninclude pixantrone (Pixuvri®, CTI Biopharma).

In some embodiments, one or more other therapeutic agent is an inhibitorof anti-apoptotic proteins, such as BCL-2. Approved anti-apoptoticswhich may be used in the present invention include venetoclax(Venclexta®, AbbVie/Genentech); and blinatumomab (Blincyto®, Amgen).Other therapeutic agents targeting apoptotic proteins which haveundergone clinical testing and may be used in the present inventioninclude navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, one or more other therapeutic agent is an androgenreceptor inhibitor. Approved androgen receptor inhibitors useful in thepresent invention include enzalutamide (Xtandi®, Astellas/Medivation);approved inhibitors of androgen synthesis include abiraterone (Zytiga®,Centocor/Ortho); approved antagonist of gonadotropin-releasing hormone(GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

In some embodiments, one or more other therapeutic agent is a selectiveestrogen receptor modulator (SERM), which interferes with the synthesisor activity of estrogens. Approved SERMs useful in the present inventioninclude raloxifene (Evista®, Eli Lilly).

In some embodiments, one or more other therapeutic agent is an inhibitorof bone resorption. An approved therapeutic which inhibits boneresorption is Denosumab (Xgeva®, Amgen), an antibody that binds toRANKL, prevents binding to its receptor RANK, found on the surface ofosteoclasts, their precursors, and osteoclast-like giant cells, whichmediates bone pathology in solid tumors with osseous metastases. Otherapproved therapeutics that inhibit bone resorption includebisphosphonates, such as zoledronic acid (Zometa®, Novartis).

In some embodiments, one or more other therapeutic agent is an inhibitorof interaction between the two primary p53 suppressor proteins, MDMX andMDM2. Inhibitors of p53 suppression proteins being studied which may beused in the present invention include ALRN-6924 (Aileron), a stapledpeptide that equipotently binds to and disrupts the interaction of MDMXand MDM2 with p53. ALRN-6924 is currently being evaluated in clinicaltrials for the treatment of AML, advanced myelodysplastic syndrome (MDS)and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agent is an inhibitorof transforming growth factor-beta (TGF-beta or TGFB). Inhibitors ofTGF-beta proteins being studied which may be used in the presentinvention include NIS793 (Novartis), an anti-TGF-beta antibody beingtested in the clinic for treatment of various cancers, including breast,lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer(NCT 02947165). In some embodiments, the inhibitor of TGF-beta proteinsis fresolimumab (GC1008; Sanofi-Genzyme), which is being studied formelanoma (NCT00923169); renal cell carcinoma (NCT00356460); andnon-small cell lung cancer (NCT02581787). Additionally, in someembodiments, the additional therapeutic agent is a TGF-beta trap, suchas described in Connolly et al. (2012) Int'l J. Biological Sciences8:964-978. One therapeutic compound currently in clinical trials fortreatment of solid tumors is M7824 (Merck KgaA—formerly MSB0011459X),which is a bispecific, anti-PD-L1/TGF8 trap compound (NCT02699515); and(NCT02517398). M7824 is comprised of a fully human IgG1 antibody againstPD-L1 fused to the extracellular domain of human TGF-beta receptor II,which functions as a TGF8 “trap.”

In some embodiments, one or more other therapeutic agent is selectedfrom glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), ananti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxicMMAE. gpNMB is a protein overexpressed by multiple tumor typesassociated with cancer cells' ability to metastasize.

In some embodiments, one or more other therapeutic agent is anantiproliferative compound. Such antiproliferative compounds include,but are not limited to aromatase inhibitors; antiestrogens;topoisomerase I inhibitors; topoisomerase II inhibitors; microtubuleactive compounds; alkylating compounds; histone deacetylase inhibitors;compounds which induce cell differentiation processes; cyclooxygenaseinhibitors; MMP inhibitors; mTOR inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity and further anti-angiogenic compounds;compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase; gonadorelin agonists; anti-androgens; methionineaminopeptidase inhibitors; matrix metalloproteinase inhibitors;bisphosphonates; biological response modifiers; antiproliferativeantibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms;telomerase inhibitors; proteasome inhibitors; compounds used in thetreatment of hematologic malignancies; compounds which target, decreaseor inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG(17-allylaminogeldanamycin, NSC330507), 17-DMAG(17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545),IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics;temozolomide (Temodal®); kinesin spindle protein inhibitors, such asSB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazinefrom CombinatoRx; MEK inhibitors such as ARRY142886 from ArrayBioPharma, AZd₆244 from AstraZeneca, PD181461 from Pfizer andleucovorin.

In some embodiments, the present invention provides a method of treatingAlzheimer's disease comprising administering to a patient in needthereof a compound of formula I and one or more additional therapeuticagents selected from donepezil (Aricept®), rivastigmine (Excelon®),galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

In some embodiments, one or more other therapeutic agent is a taxanecompound, which causes disruption of microtubules, which are essentialfor cell division. In some embodiments, a taxane compound is selectedfrom paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®,Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel(Abraxane®; Abraxis/Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis),and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, one or more other therapeutic agent is a nucleosideinhibitor, or a therapeutic agent that interferes with normal DNAsynthesis, protein synthesis, cell replication, or will otherwiseinhibit rapidly proliferating cells.

In some embodiments, a nucleoside inhibitor is selected from trabectedin(guanidine alkylating agent, Yondelis®, Janssen Oncology),mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals);vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals;Marqibo®, Talon Therapeutics); temozolomide (prodrug to alkylating agent5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®,Merck); cytarabine injection (ara-C, antimetabolic cytidine analog,Pfizer); lomustine (alkylating agent, CeeNU®, Bristol-Myers Squibb;Gleostine®, NextSource Biotechnology); azacitidine (pyrimidinenucleoside analog of cytidine, Vidaza®, Celgene); omacetaxinemepesuccinate (cephalotaxine ester) (protein synthesis inhibitor,Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi(enzyme for depletion of asparagine, Elspar®, Lundbeck; Erwinaze®, EUSAPharma); eribulin mesylate (microtubule inhibitor, tubulin-basedantimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor,tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrine(thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine(bifunctional mechlorethamine derivative, believed to form interstrandDNA cross-links, Treanda®, Cephalon/Teva); ixabepilone (semi-syntheticanalog of epothilone B, microtubule inhibitor, tubulin-basedantimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug ofdeoxyguanosine analog, nucleoside metabolic inhibitor, Arranon®,Novartis); clorafabine (prodrug of ribonucleotide reductase inhibitor,competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); andtrifluridine and tipiracil (thymidine-based nucleoside analog andthymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology).

In some embodiments, one or more other therapeutic agent is a kinaseinhibitor or VEGF-R antagonist. Approved VEGF inhibitors and kinaseinhibitors useful in the present invention include: bevacizumab(Avastin®, Genentech/Roche) an anti-VEGF monoclonal antibody;ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody andziv-aflibercept, also known as VEGF Trap (Zaltrap®; Regeneron/Sanofi).VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib(Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib(Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AGand Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®,Genentech/Roche); MEK inhibitors, such as cobimetanib (Cotellic®,Exelexis/Genentech/Roche); trametinib (Mekinist®, Novartis); Bcr-Abltyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis);nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®,BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib(Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such asgefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®,Genentech/Roche/Astellas); lapatinib (Tykerb®, Novartis); afatinib(Gilotrif®, Boehringer Ingelheim); osimertinib (targeting activatedEGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, AriadPharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib(Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib(Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, suchas crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); andalectinib (Alecenza®, Genentech/Roche); Bruton's tyrosine kinaseinhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics/Janssen); andFlt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

Other kinase inhibitors and VEGF-R antagonists that are in developmentand may be used in the present invention include tivozanib (AveoPharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (ClovisOncology); dovitinib (TK1258, Novartis); Chiauanib (ChipscreenBiosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories);neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511,Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, IncyteCorporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib(Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib(Amgen/Takeda).

In another embodiment, the present invention provides a method oftreating organ transplant rejection or graft vs. host disease comprisingadministering to a patient in need thereof a compound of formula I andone or more additional therapeutic agents selected from a steroid,cyclosporin, FK506, rapamycin, a hedgehog signaling inhibitor, a BTKinhibitor, a JAK/pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor,and a SYK inhibitor.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a BTKinhibitor, wherein the disease is selected from inflammatory boweldisease, arthritis, systemic lupus erythematosus (SLE), vasculitis,idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis,psoriatic arthritis, osteoarthritis, Still's disease, juvenilearthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord'sthyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren'ssyndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis,Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison'sdisease, opsoclonus-myoclonus syndrome, ankylosing spondylosis,antiphospholipid antibody syndrome, aplastic anemia, autoimmunehepatitis, autoimmune gastritis, pernicious anemia, celiac disease,Goodpasture's syndrome, idiopathic thrombocytopenic purpura, opticneuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome,Takayasu's arteritis, temporal arteritis, warm autoimmune hemolyticanemia, Wegener's granulomatosis, psoriasis, alopecia universalis,Behcet's disease, chronic fatigue, dysautonomia, membranousglomerulonephropathy, endometriosis, interstitial cystitis, pemphigusvulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, ahyperproliferative disease, rejection of transplanted organs or tissues,Acquired Immunodeficiency Syndrome (AIDS, also known as HIV), type 1diabetes, graft versus host disease, transplantation, transfusion,anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs,foods, insect poisons, animal hair, animal dander, dust mites, orcockroach calyx), type I hypersensitivity, allergic conjunctivitis,allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, Crohn's disease, cystitis,dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis,endometritis, enteritis, enterocolitis, epicondylitis, epididymitis,fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonleinpurpura, hepatitis, hidradenitis suppurativa, immunoglobulin Anephropathy, interstitial lung disease, laryngitis, mastitis,meningitis, myelitis myocarditis, myositis, nephritis, oophoritis,orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia,polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cellproliferative disorder, e.g., diffuse large B cell lymphoma, follicularlymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia,acute lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, multiple myeloma (also known as plasma cellmyeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma,extranodal marginal zone B cell lymphoma, nodal marginal zone B celllymphoma, mantle cell lymphoma, mediastinal (thymic) large B celllymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, Burkitt lymphoma/leukemia, or lymphomatoid granulomatosis,breast cancer, prostate cancer, or cancer of the mast cells (e.g.,mastocytoma, mast cell leukemia, mast cell sarcoma, systemicmastocytosis), bone cancer, colorectal cancer, pancreatic cancer,diseases of the bone and joints including, without limitation,rheumatoid arthritis, seronegative spondyloarthropathies (includingankylosing spondylitis, psoriatic arthritis and Reiter's disease),Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis,bone cancer, bone metastasis, a thromboembolic disorder, (e.g.,myocardial infarct, angina pectoris, reocclusion after angioplasty,restenosis after angioplasty, reocclusion after aortocoronary bypass,restenosis after aortocoronary bypass, stroke, transitory ischemia, aperipheral arterial occlusive disorder, pulmonary embolism, deep venousthrombosis), inflammatory pelvic disease, urethritis, skin sunburn,sinusitis, pneumonitis, encephalitis, meningitis, myocarditis,nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis,dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitus,agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection,hyperacute rejection of transplanted organs, asthma, allergic rhinitis,chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease (also known as autoimmune polyglandular syndrome), autoimmunealopecia, pernicious anemia, glomerulonephritis, dermatomyositis,multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic andthrombocytopenic states, Goodpasture's syndrome, atherosclerosis,Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes,septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,psoriatic arthritis, juvenile arthritis, osteoarthritis, chronicidiopathic thrombocytopenic purpura, Waldenstrom macroglobulinemia,myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis,degenerative joint disease, vitiligo, autoimmune hypopituitarism,Guillain-Barre syndrome, Behcet's disease, scleraderma, mycosisfungoides, acute inflammatory responses (such as acute respiratorydistress syndrome and ischemia/reperfusion injury), and Graves' disease.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from a cancer, aneurodegenative disorder, an angiogenic disorder, a viral disease, anautoimmune disease, an inflammatory disorder, a hormone-related disease,conditions associated with organ transplantation, immunodeficiencydisorders, a destructive bone disorder, a proliferative disorder, aninfectious disease, a condition associated with cell death,thrombin-induced platelet aggregation, chronic myelogenous leukemia(CML), chronic lymphocytic leukemia (CLL), liver disease, pathologicimmune conditions involving T cell activation, a cardiovasculardisorder, and a CNS disorder.

In another embodiment, the present invention provides a method oftreating or lessening the severity of a disease comprising administeringto a patient in need thereof a compound of formula I and a PI3Kinhibitor, wherein the disease is selected from benign or malignanttumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cellcarcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach,gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung,vagina, endometrium, cervix, testis, genitourinary tract, esophagus,larynx, skin, bone or thyroid, sarcoma, glioblastomas, neuroblastomas,multiple myeloma or gastrointestinal cancer, especially colon carcinomaor colorectal adenoma or a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia, aneoplasia of epithelial character, adenoma, adenocarcinoma,keratoacanthoma, epidermoid carcinoma, large cell carcinoma,non-small-cell lung carcinoma, lymphomas, (including, for example,non-Hodgkin's Lymphoma (NHL) and Hodgkin's lymphoma (also termedHodgkin's or Hodgkin's disease)), a mammary carcinoma, follicularcarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma,melanoma, or a leukemia, diseases include Cowden syndrome,Lhermitte-Dudos disease and Bannayan-Zonana syndrome, or diseases inwhich the PI3K/PKB pathway is aberrantly activated, asthma of whatevertype or genesis including both intrinsic (non-allergic) asthma andextrinsic (allergic) asthma, mild asthma, moderate asthma, severeasthma, bronchitic asthma, exercise-induced asthma, occupational asthmaand asthma induced following bacterial infection, acute lung injury(ALI), adult/acute respiratory distress syndrome (ARDS), chronicobstructive pulmonary, airways or lung disease (COPD, COAD or COLD),including chronic bronchitis or dyspnea associated therewith, emphysema,as well as exacerbation of airways hyperreactivity consequent to otherdrug therapy, in particular other inhaled drug therapy, bronchitis ofwhatever type or genesis including, but not limited to, acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis,pneumoconiosis (an inflammatory, commonly occupational, disease of thelungs, frequently accompanied by airways obstruction, whether chronic oracute, and occasioned by repeated inhalation of dusts) of whatever typeor genesis, including, for example, aluminosis, anthracosis, asbestosis,chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis,Loffler's syndrome, eosinophilic, pneumonia, parasitic (in particularmetazoan) infestation (including tropical eosinophilia),bronchopulmonary aspergillosis, polyarteritis nodosa (includingChurg-Strauss syndrome), eosinophilic granuloma and eosinophil-relateddisorders affecting the airways occasioned by drug-reaction, psoriasis,contact dermatitis, atopic dermatitis, alopecia areata, erythemamultiforma, dermatitis herpetiformis, scleroderma, vitiligo,hypersensitivity angiitis, urticaria, bullous pemphigoid, lupuserythematosus, pemphisus, epidermolysis bullosa acquisita,conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis,diseases affecting the nose including allergic rhinitis, andinflammatory disease in which autoimmune reactions are implicated orhaving an autoimmune component or etiology, including autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegenergranulamatosis, dermatomyositis, chronic active hepatitis, myastheniagravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), endocrine opthalmopathy, Grave's disease, sarcoidosis,alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis,primary biliary cirrhosis, uveitis (anterior and posterior),keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitiallung fibrosis, psoriatic arthritis and glomerulonephritis (with andwithout nephrotic syndrome, e.g. including idiopathic nephrotic syndromeor minal change nephropathy, restenosis, cardiomegaly, atherosclerosis,myocardial infarction, ischemic stroke and congestive heart failure,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, and cerebral ischemia, and neurodegenerativedisease caused by traumatic injury, glutamate neurotoxicity and hypoxia.

In some embodiments, one or more other therapeutic agent is aphosphatidylinositol 3 kinase (PI3K) inhibitor. In some embodiments, aPI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib(BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche); pictilisib(GDC-0941, Genentech/Roche); copanlisib (BAY806946, Bayer); duvelisib(formerly IPI-145, Infinity Pharmaceuticals); PQR309 (PiqurTherapeutics, Switzerland); and TGR1202 (formerly RP5230, TGTherapeutics).

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of acancer, an autoimmune disorder, a proliferative disorder, aninflammatory disorder, a neurodegenerative or neurological disorder,schizophrenia, a bone-related disorder, liver disease, or a cardiacdisorder. The exact amount required will vary from subject to subject,depending on the species, age, and general condition of the subject, theseverity of the infection, the particular agent, its mode ofadministration, and the like. Compounds of the invention are preferablyformulated in dosage unit form for ease of administration and uniformityof dosage. The expression “dosage unit form” as used herein refers to aphysically discrete unit of agent appropriate for the patient to betreated. It will be understood, however, that the total daily usage ofthe compounds and compositions of the present invention will be decidedby the attending physician within the scope of sound medical judgment.The specific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

Pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtrationthrough a bacterial-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedor dispersed in sterile water or other sterile injectable medium priorto use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, and eye drops are also contemplatedas being within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

According to one embodiment, the invention relates to a method ofinhibiting protein kinase activity or degrading a protein kinase in abiological sample comprising the step of contacting said biologicalsample with a compound of this invention, or a composition comprisingsaid compound.

According to another embodiment, the invention relates to a method ofinhibiting or degrading IRAK-1, IRAK-2, and/or IRAK-4, or a mutantthereof, activity in a biological sample comprising the step ofcontacting said biological sample with a compound of this invention, ora composition comprising said compound.

The term “biological sample”, as used herein, includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition and/or degradation of a protein kinase, or a protein kinaseselected from IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof,activity in a biological sample is useful for a variety of purposes thatare known to one of skill in the art. Examples of such purposes include,but are not limited to, blood transfusion, organ-transplantation,biological specimen storage, and biological assays.

Another embodiment of the present invention relates to a method ofdegrading a protein kinase and/or inhibiting protein kinase activity ina patient comprising the step of administering to said patient acompound of the present invention, or a composition comprising saidcompound.

According to another embodiment, the invention relates to a method ofdegrading and/or inhibiting one or more of IRAK-1, IRAK-2, and/orIRAK-4, or a mutant thereof, activity in a patient comprising the stepof administering to said patient a compound of the present invention, ora composition comprising said compound. In other embodiments, thepresent invention provides a method for treating a disorder mediated byone or more of IRAK-1, IRAK-2, and/or IRAK-4, or a mutant thereof, in apatient in need thereof, comprising the step of administering to saidpatient a compound according to the present invention orpharmaceutically acceptable composition thereof. Such disorders aredescribed in detail herein.

Depending upon the particular condition, or disease, to be treated,additional therapeutic agents that are normally administered to treatthat condition, may also be present in the compositions of thisinvention. As used herein, additional therapeutic agents that arenormally administered to treat a particular disease, or condition, areknown as “appropriate for the disease, or condition, being treated.”

A compound of the current invention may also be used to advantage incombination with other antiproliferative compounds. Suchantiproliferative compounds include, but are not limited to aromataseinhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase IIinhibitors; microtubule active compounds; alkylating compounds; histonedeacetylase inhibitors; compounds which induce cell differentiationprocesses; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors;antineoplastic antimetabolites; platin compounds; compoundstargeting/decreasing a protein or lipid kinase activity and furtheranti-angiogenic compounds; compounds which target, decrease or inhibitthe activity of a protein or lipid phosphatase; gonadorelin agonists;anti-androgens; methionine aminopeptidase inhibitors; matrixmetalloproteinase inhibitors; bisphosphonates; biological responsemodifiers; antiproliferative antibodies; heparanase inhibitors;inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasomeinhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of Flt-3; Hsp90inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507),17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin,NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from ConformaTherapeutics; temozolomide (Temodal®); kinesin spindle proteininhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, orpentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such asARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 fromPfizer and leucovorin.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits estrogen production, for instance, the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane is marketed under thetrade name Aromasin™. Formestane is marketed under the trade nameLentaron™. Fadrozole is marketed under the trade name Afema™.Anastrozole is marketed under the trade name Arimidex™. Letrozole ismarketed under the trade names Femara™ or Femar™. Aminoglutethimide ismarketed under the trade name Orimeten™. A combination of the inventioncomprising a chemotherapeutic agent which is an aromatase inhibitor isparticularly useful for the treatment of hormone receptor positivetumors, such as breast tumors.

In some embodiments, one or more other therapeutic agent is an mTORinhibitor, which inhibits cell proliferation, angiogenesis and glucoseuptake. In some embodiments, an mTOR inhibitor is everolimus (Afinitor®,Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®,Pfizer).

In some embodiments, one or more other therapeutic agent is an aromataseinhibitor. In some embodiments, an aromatase inhibitor is selected fromexemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca) andletrozole (Femara®, Novartis).

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen is marketed under the trade nameNolvadex™. Raloxifene hydrochloride is marketed under the trade nameEvista™. Fulvestrant can be administered under the trade name Faslodex™.A combination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, such as breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (Casodex™) The term“gonadorelin agonist” as used herein includes, but is not limited toabarelix, goserelin and goserelin acetate. Goserelin can be administeredunder the trade name Zoladex™.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148. Irinotecan can be administered, e.g. in the formas it is marketed, e.g. under the trademark Camptosar™. Topotecan ismarketed under the trade name Hycamptin™.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, such as Caelyx™), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide is marketed under the trade name Etopophos™. Teniposide ismarketed under the trade name VM 26-Bristol Doxorubicin is marketedunder the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketedunder the trade name Farmorubicin™. Idarubicin is marketed. under thetrade name Zavedos™. Mitoxantrone is marketed under the trade nameNovantron.

The term “microtubule active agent” relates to microtubule stabilizing,microtubule destabilizing compounds and microtublin polymerizationinhibitors including, but not limited to taxanes, such as paclitaxel anddocetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate,vincristine or vincristine sulfate, and vinorelbine; discodermolides;cochicine and epothilones and derivatives thereof. Paclitaxel ismarketed under the trade name Taxol™. Docetaxel is marketed under thetrade name Taxotere™. Vinblastine sulfate is marketed under the tradename Vinblastin R.P™. Vincristine sulfate is marketed under the tradename Farmistin™.

The term “alkylating agent” as used herein includes, but is not limitedto, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU orGliadel). Cyclophosphamide is marketed under the trade name Cyclostin™.Ifosfamide is marketed under the trade name Holoxan™.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes, but is not limited to,suberoylanilide hydroxamic acid (SAHA).

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabineis marketed under the trade name Xeloda™. Gemcitabine is marketed underthe trade name Gemzar™.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g., in the form as it is marketed, e.g. under thetrademark Carboplat™. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark Eloxatin™.

The term “Bcl-2 inhibitor” as used herein includes, but is not limitedto compounds having inhibitory activity against B-cell lymphoma 2protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737,apogossypol, Ascenta's pan-Bcl-2 inhibitors, curcumin (and analogsthereof), dual Bcl-2/Bcl-xL inhibitors (InfinityPharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1(and analogs thereof; see WO2008118802), navitoclax (and analogsthereof, see U.S. Pat. No. 7,390,799), NH-1 (Shenayng PharmaceuticalUniversity), obatoclax (and analogs thereof, see WO2004106328), S-001(Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), andvenetoclax. In some embodiments the Bcl-2 inhibitor is a small moleculetherapeutic. In some embodiments the Bcl-2 inhibitor is apeptidomimetic.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity; or a protein or lipid phosphatase activity; or furtheranti-angiogenic compounds” as used herein includes, but is not limitedto, protein tyrosine kinase and/or serine and/or threonine kinaseinhibitors or lipid kinase inhibitors, such as a) compounds targeting,decreasing or inhibiting the activity of the platelet-derived growthfactor-receptors (PDGFR), such as compounds which target, decrease orinhibit the activity of PDGFR, especially compounds which inhibit thePDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, suchas imatinib, SU101, SU6668 and GFB-111; b) compounds targeting,decreasing or inhibiting the activity of the fibroblast growthfactor-receptors (FGFR); c) compounds targeting, decreasing orinhibiting the activity of the insulin-like growth factor receptor I(IGF-IR), such as compounds which target, decrease or inhibit theactivity of IGF-IR, especially compounds which inhibit the kinaseactivity of IGF-I receptor, or antibodies that target the extracellulardomain of IGF-I receptor or its growth factors; d) compounds targeting,decreasing or inhibiting the activity of the Trk receptor tyrosinekinase family, or ephrin B4 inhibitors; e) compounds targeting,decreasing or inhibiting the activity of the AxI receptor tyrosinekinase family; f) compounds targeting, decreasing or inhibiting theactivity of the Ret receptor tyrosine kinase; g) compounds targeting,decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosinekinase, such as imatinib; h) compounds targeting, decreasing orinhibiting the activity of the C-kit receptor tyrosine kinases, whichare part of the PDGFR family, such as compounds which target, decreaseor inhibit the activity of the c-Kit receptor tyrosine kinase family,especially compounds which inhibit the c-Kit receptor, such as imatinib;i) compounds targeting, decreasing or inhibiting the activity of membersof the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase)and mutants, such as compounds which target decrease or inhibit theactivity of c-Abl family members and their gene fusion products, such asan N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib(AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; ordasatinib (BMS-354825); j) compounds targeting, decreasing or inhibitingthe activity of members of the protein kinase C (PKC) and Raf family ofserine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK,PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/ormembers of the cyclin-dependent kinase family (CDK) includingstaurosporine derivatives, such as midostaurin; examples of furthercompounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1,Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; ll sis 3521;LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (aPI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting,decreasing or inhibiting the activity of protein-tyrosine kinaseinhibitors, such as compounds which target, decrease or inhibit theactivity of protein-tyrosine kinase inhibitors include imatinib mesylate(Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99;Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; TyrphostinB44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494;Tyrphostin AG 556, AG957 and adaphostin(4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester;NSC 680410, adaphostin); 1) compounds targeting, decreasing orinhibiting the activity of the epidermal growth factor family ofreceptor tyrosine kinases (EGFR₁ ErbB2, ErbB3, ErbB4 as homo- orheterodimers) and their mutants, such as compounds which target,decrease or inhibit the activity of the epidermal growth factor receptorfamily are especially compounds, proteins or antibodies which inhibitmembers of the EGF receptor tyrosine kinase family, such as EGFreceptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands,CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab(Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1,E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting,decreasing or inhibiting the activity of the c-Met receptor, such ascompounds which target, decrease or inhibit the activity of c-Met,especially compounds which inhibit the kinase activity of c-Metreceptor, or antibodies that target the extracellular domain of c-Met orbind to HGF, n) compounds targeting, decreasing or inhibiting the kinaseactivity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/orpan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib,pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, andruxolitinib; o) compounds targeting, decreasing or inhibiting the kinaseactivity of PI3 kinase (PI3K) including but not limited to ATU-027,SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib,pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, andidelalisib; and; and q) compounds targeting, decreasing or inhibitingthe signaling effects of hedgehog protein (Hh) or smoothened receptor(SMO) pathways, including but not limited to cyclopamine, vismodegib,itraconazole, erismodegib, and IPI-926 (saridegib).

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

In some embodiments, one or more other therapeutic agent is a growthfactor antagonist, such as an antagonist of platelet-derived growthfactor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR).Approved PDGF antagonists which may be used in the present inventioninclude olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonistswhich may be used in the present invention include cetuximab (Erbitux®,Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®,Amgen); and osimertinib (targeting activated EGFR, Tagrisso®,AstraZeneca).

The term “PI3K inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against one or more enzymes in thephosphatidylinositol-3-kinase family, including, but not limited toPI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α,p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87.Examples of PI3K inhibitors useful in this invention include but are notlimited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474,buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147,XL-765, and idelalisib.

The term “BTK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against Bruton's Tyrosine Kinase(BTK), including, but not limited to AVL-292 and ibrutinib.

The term “SYK inhibitor” as used herein includes, but is not limited tocompounds having inhibitory activity against spleen tyrosine kinase(SYK), including but not limited to PRT-062070, R-343, R-333, Excellair,PRT-062607, and fostamatinib

Further examples of BTK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2008039218 and WO2011090760, the entirety of which areincorporated herein by reference.

Further examples of SYK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2003063794, WO2005007623, and WO2006078846, the entirety ofwhich are incorporated herein by reference.

Further examples of PI3K inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2004019973, WO2004089925, WO2007016176, U.S. Pat. No.8,138,347, WO2002088112, WO2007084786, WO2007129161, WO2006122806,WO2005113554, and WO2007044729 the entirety of which are incorporatedherein by reference.

Further examples of JAK inhibitory compounds, and conditions treatableby such compounds in combination with compounds of this invention can befound in WO2009114512, WO2008109943, WO2007053452, WO2000142246, andWO2007070514, the entirety of which are incorporated herein byreference.

Further anti-angiogenic compounds include compounds having anothermechanism for their activity, e.g. unrelated to protein or lipid kinaseinhibition e.g. thalidomide (Thalomid™) and TNP-470.

Examples of proteasome inhibitors useful for use in combination withcompounds of the invention include, but are not limited to bortezomib,disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A,carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds which target, decrease or inhibit the activity of a protein orlipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A,or CDC25, such as okadaic acid or a derivative thereof.

Compounds which induce cell differentiation processes include, but arenot limited to, retinoic acid, α- γ- or δ-tocopherol or α- γ- orδ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is notlimited to, Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, such as5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. Etridonic acid is marketedunder the trade name Didronel™. Clodronic acid is marketed under thetrade name Bonefos™. Tiludronic acid is marketed under the trade nameSkelid™. Pamidronic acid is marketed under the trade name Aredia™.Alendronic acid is marketed under the trade name Fosamax™. Ibandronicacid is marketed under the trade name Bondranat™. Risedronic acid ismarketed under the trade name Actonel™. Zoledronic acid is marketedunder the trade name Zometa™. The term “mTOR inhibitors” relates tocompounds which inhibit the mammalian target of rapamycin (mTOR) andwhich possess antiproliferative activity such as sirolimus (Rapamune®),everolimus (Certican™), CCI-779 and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88. The term “biological responsemodifier” as used herein refers to a lymphokine or interferons.

The term “inhibitor of Ras oncogenic isoforms”, such as H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras; for example, a “farnesyltransferase inhibitor” such as L-744832, DK8G557 or R115777(Zarnestra™). The term “telomerase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of telomerase.Compounds which target, decrease or inhibit the activity of telomeraseare especially compounds which inhibit the telomerase receptor, such astelomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase include, but are not limited to, bengamideor a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasomeinclude, but are not limited to, Bortezomib (Velcade™), ); carfilzomib(Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors, which are compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors,which are compounds which target, decrease or inhibit anaplasticlymphoma kinase.

Compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R) are especially compounds, proteins orantibodies which inhibit members of the Flt-3R receptor kinase family,such as PKC412, midostaurin, a staurosporine derivative, SU11248 andMLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; othergeldanamycin related compounds; radicicol and HDAC inhibitors.

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™), rituximab (Rituxan®), PR064553 (anti-CD40) and2C4 Antibody. By antibodies is meant intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

For the treatment of acute myeloid leukemia (AML), compounds of thecurrent invention can be used in combination with standard leukemiatherapies, especially in combination with therapies used for thetreatment of AML. In particular, compounds of the current invention canbe administered in combination with, for example, farnesyl transferaseinhibitors and/or other drugs useful for the treatment of AML, such asDaunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone,Idarubicin, Carboplatinum and PKC412.

Other anti-leukemic compounds include, for example, Ara-C, a pyrimidineanalog, which is the 2′-alpha-hydroxy ribose (arabinoside) derivative ofdeoxycytidine. Also included is the purine analog of hypoxanthine,6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds whichtarget, decrease or inhibit activity of histone deacetylase (HDAC)inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid(SAHA) inhibit the activity of the enzymes known as histonedeacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228(formerly FR901228), Trichostatin A and compounds disclosed in U.S. Pat.No. 6,552,065 including, but not limited to,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt. Somatostatin receptor antagonists as used herein refer tocompounds which target, treat or inhibit the somatostatin receptor suchas octreotide, and SOM230. Tumor cell damaging approaches refer toapproaches such as ionizing radiation. The term “ionizing radiation”referred to above and hereinafter means ionizing radiation that occursas either electromagnetic rays (such as X-rays and gamma rays) orparticles (such as alpha and beta particles). Ionizing radiation isprovided in, but not limited to, radiation therapy and is known in theart. See Hellman, Principles of Radiation Therapy, Cancer, in Principlesand Practice of Oncology, Devita et al., Eds., 4′ Edition, Vol. 1, pp.248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors.The term “EDG binders” as used herein refers to a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFTY720. The term “ribonucleotide reductase inhibitors” refers topyrimidine or purine nucleoside analogs including, but not limited to,fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine,5-fluorouracil, cladribine, 6-mercaptopurine (especially in combinationwith ara-C against ALL) and/or pentostatin. Ribonucleotide reductaseinhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also included are in particular those compounds, proteins or monoclonalantibodies of VEGF such as1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof,1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate;Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; ZD6474;SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGFreceptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such asMacugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgG1 antibody,Angiozyme (RPI 4610) and Bevacizumab (Avastin™)

Photodynamic therapy as used herein refers to therapy which uses certainchemicals known as photosensitizing compounds to treat or preventcancers. Examples of photodynamic therapy include treatment withcompounds, such as Visudyne™ and porfimer sodium.

Angiostatic steroids as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone,hydrocortisone, 11-α-epihydrocotisol, cortexolone,17a-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

Implants containing corticosteroids refers to compounds, such asfluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plantalkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with other drug substances such asanti-inflammatory, bronchodilatory or antihistamine drug substances,particularly in the treatment of obstructive or inflammatory airwaysdiseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Acompound of the invention may be mixed with the other drug substance ina fixed pharmaceutical composition or it may be administered separately,before, simultaneously with or after the other drug substance.Accordingly the invention includes a combination of a compound of theinvention as hereinbefore described with an anti-inflammatory,bronchodilatory, antihistamine or anti-tussive drug substance, saidcompound of the invention and said drug substance being in the same ordifferent pharmaceutical composition.

Suitable anti-inflammatory drugs include steroids, in particularglucocorticosteroids such as budesonide, beclamethasone dipropionate,fluticasone propionate, ciclesonide or mometasone furoate; non-steroidalglucocorticoid receptor agonists; LTB4 antagonists such LY293111,CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4antagonists such as montelukast and zafirlukast; PDE4 inhibitors suchcilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A(Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline(Almirall Prodesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SeICID™CC-10004 (Celgene), VM554/UM565(Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo); A2a agonists;A2b antagonists; and beta-2 adrenoceptor agonists such as albuterol(salbutamol), metaproterenol, terbutaline, salmeterol fenoterol,procaterol, and especially, formoterol and pharmaceutically acceptablesalts thereof. Suitable bronchodilatory drugs include anticholinergic orantimuscarinic compounds, in particular ipratropium bromide, oxitropiumbromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine.

Other useful combinations of compounds of the invention withanti-inflammatory drugs are those with antagonists of chemokinereceptors, e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8,CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 andSCH-D, and Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminiumchloride (TAK-770).

The structure of the active compounds identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications).

A compound of the current invention may also be used in combination withknown therapeutic processes, for example, the administration of hormonesor radiation. In certain embodiments, a provided compound is used as aradiosensitizer, especially for the treatment of tumors which exhibitpoor sensitivity to radiotherapy.

A compound of the current invention can be administered alone or incombination with one or more other therapeutic compounds, possiblecombination therapy taking the form of fixed combinations or theadministration of a compound of the invention and one or more othertherapeutic compounds being staggered or given independently of oneanother, or the combined administration of fixed combinations and one ormore other therapeutic compounds. A compound of the current inventioncan besides or in addition be administered especially for tumor therapyin combination with chemotherapy, radiotherapy, immunotherapy,phototherapy, surgical intervention, or a combination of these.Long-term therapy is equally possible as is adjuvant therapy in thecontext of other treatment strategies, as described above. Otherpossible treatments are therapy to maintain the patient's status aftertumor regression, or even chemopreventive therapy, for example inpatients at risk.

Those additional agents may be administered separately from an inventivecompound-containing composition, as part of a multiple dosage regimen.Alternatively, those agents may be part of a single dosage form, mixedtogether with a compound of this invention in a single composition. Ifadministered as part of a multiple dosage regime, the two active agentsmay be submitted simultaneously, sequentially or within a period of timefrom one another normally within five hours from one another.

As used herein, the term “combination,” “combined,” and related termsrefers to the simultaneous or sequential administration of therapeuticagents in accordance with this invention. For example, a compound of thepresent invention may be administered with another therapeutic agentsimultaneously or sequentially in separate unit dosage forms or togetherin a single unit dosage form. Accordingly, the present inventionprovides a single unit dosage form comprising a compound of the currentinvention, an additional therapeutic agent, and a pharmaceuticallyacceptable carrier, adjuvant, or vehicle.

The amount of both an inventive compound and additional therapeuticagent (in those compositions which comprise an additional therapeuticagent as described above) that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. Preferably,compositions of this invention should be formulated so that a dosage ofbetween 0.01-100 mg/kg body weight/day of an inventive compound can beadministered.

In those compositions which comprise an additional therapeutic agent,that additional therapeutic agent and the compound of this invention mayact synergistically. Therefore, the amount of additional therapeuticagent in such compositions will be less than that required in amonotherapy utilizing only that therapeutic agent. In such compositionsa dosage of between 0.01-1,000 μg/kg body weight/day of the additionaltherapeutic agent can be administered.

The amount of one or more other therapeutic agent present in thecompositions of this invention may be no more than the amount that wouldnormally be administered in a composition comprising that therapeuticagent as the only active agent. Preferably the amount of one or moreother therapeutic agent in the presently disclosed compositions willrange from about 50% to 100% of the amount normally present in acomposition comprising that agent as the only therapeutically activeagent. In some embodiments, one or more other therapeutic agent isadministered at a dosage of about 50%, about 55%, about 60%, about 65%,about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% ofthe amount normally administered for that agent. As used herein, thephrase “normally administered” means the amount an FDA approvedtherapeutic agent is approvided for dosing per the FDA label insert.

The compounds of this invention, or pharmaceutical compositions thereof,may also be incorporated into compositions for coating an implantablemedical device, such as prostheses, artificial valves, vascular grafts,stents and catheters. Vascular stents, for example, have been used toovercome restenosis (re-narrowing of the vessel wall after injury).However, patients using stents or other implantable devices risk clotformation or platelet activation. These unwanted effects may beprevented or mitigated by pre-coating the device with a pharmaceuticallyacceptable composition comprising a kinase inhibitor. Implantabledevices coated with a compound of this invention are another embodimentof the present invention.

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agent is animmuno-oncology agent. As used herein, the term “an immuno-oncologyagent” refers to an agent which is effective to enhance, stimulate,and/or up-regulate immune responses in a subject. In some embodiments,the administration of an immuno-oncology agent with a compound of theinvention has a synergic effect in treating a cancer.

An immuno-oncology agent can be, for example, a small molecule drug, anantibody, or a biologic or small molecule. Examples of biologicimmuno-oncology agents include, but are not limited to, cancer vaccines,antibodies, and cytokines. In some embodiments, an antibody is amonoclonal antibody. In some embodiments, a monoclonal antibody ishumanized or human.

In some embodiments, an immuno-oncology agent is (i) an agonist of astimulatory (including a co-stimulatory) receptor or (ii) an antagonistof an inhibitory (including a co-inhibitory) signal on T cells, both ofwhich result in amplifying antigen-specific T cell responses.

Certain of the stimulatory and inhibitory molecules are members of theimmunoglobulin super family (IgSF). One important family ofmembrane-bound ligands that bind to co-stimulatory or co-inhibitoryreceptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1),B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6.Another family of membrane bound ligands that bind to co-stimulatory orco-inhibitory receptors is the TNF family of molecules that bind tocognate TNF receptor family members, which includes CD40 and CD40L,OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB),TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK,RANKL, TWEAKR/Fnl4, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR,LIGHT, DcR3, HVEM, VEGI/TL1A, TRAMP/DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1,Lymphotoxin α/TNFβ, TNFR2, TNFα, LTβR, Lymphotoxin al P2, FAS, FASL,RELT, DR6, TROY, NGFR.

In some embodiments, an immuno-oncology agent is a cytokine thatinhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and otherimmunosuppressive cytokines) or a cytokine that stimulates T cellactivation, for stimulating an immune response.

In some embodiments, a combination of a compound of the invention and animmuno-oncology agent can stimulate T cell responses. In someembodiments, an immuno-oncology agent is: (i) an antagonist of a proteinthat inhibits T cell activation (e.g., immune checkpoint inhibitors)such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1,BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP,PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein thatstimulates T cell activation such as B7-1, B7-2, CD28, 4-1BB (CD137),4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3and CD28H.

In some embodiments, an immuno-oncology agent is an antagonist ofinhibitory receptors on NK cells or an agonists of activating receptorson NK cells. In some embodiments, an immuno-oncology agent is anantagonists of KIR, such as lirilumab.

In some embodiments, an immuno-oncology agent is an agent that inhibitsor depletes macrophages or monocytes, including but not limited toCSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155(WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716,WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, an immuno-oncology agent is selected from agonisticagents that ligate positive costimulatory receptors, blocking agentsthat attenuate signaling through inhibitory receptors, antagonists, andone or more agents that increase systemically the frequency ofanti-tumor T cells, agents that overcome distinct immune suppressivepathways within the tumor microenvironment (e.g., block inhibitoryreceptor engagement (e.g., PD-L1/PD-1 interactions), deplete or inhibitTregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab)or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes suchas IDO, or reverse/prevent T cell energy or exhaustion) and agents thattrigger innate immune activation and/or inflammation at tumor sites.

In some embodiments, an immuno-oncology agent is a CTLA-4 antagonist. Insome embodiments, a CTLA-4 antagonist is an antagonistic CTLA-4antibody. In some embodiments, an antagonistic CTLA-4 antibody is YERVOY(ipilimumab) or tremelimumab.

In some embodiments, an immuno-oncology agent is a PD-1 antagonist. Insome embodiments, a PD-1 antagonist is administered by infusion. In someembodiments, an immuno-oncology agent is an antibody or anantigen-binding portion thereof that binds specifically to a ProgrammedDeath-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments,a PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments,an antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA(pembrolizumab), or MEDI-0680 (AMP-514; WO2012/145493). In someembodiments, an immuno-oncology agent may be pidilizumab (CT-011). Insome embodiments, an immuno-oncology agent is a recombinant proteincomposed of the extracellular domain of PD-L2 (B7-DC) fused to the Fcportion of IgG1, called AMP-224.

In some embodiments, an immuno-oncology agent is a PD-L1 antagonist. Insome embodiments, a PD-L1 antagonist is an antagonistic PD-L1 antibody.In some embodiments, a PD-L1 antibody is MPDL3280A (RG7446;WO2010/077634), durvalumab (MED14736), BMS-936559 (WO2007/005874), andMSB0010718C (WO2013/79174).

In some embodiments, an immuno-oncology agent is a LAG-3 antagonist. Insome embodiments, a LAG-3 antagonist is an antagonistic LAG-3 antibody.In some embodiments, a LAG3 antibody is BMS-986016 (WO10/19570,WO14/08218), or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, an immuno-oncology agent is a CD137 (4-1BB)agonist. In some embodiments, a CD137 (4-1BB) agonist is an agonisticCD137 antibody. In some embodiments, a CD137 antibody is urelumab orPF-05082566 (WO12/32433).

In some embodiments, an immuno-oncology agent is a GITR agonist. In someembodiments, a GITR agonist is an agonistic GITR antibody. In someembodiments, a GITR antibody is BMS-986153, BMS-986156, TRX-518(WO006/105021, WO009/009116), or MK-4166 (WO11/028683).

In some embodiments, an immuno-oncology agent is an indoleamine(2,3)-dioxygenase (IDO) antagonist. In some embodiments, an IDOantagonist is selected from epacadostat (INCB024360, Incyte); indoximod(NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis);GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287(Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme thatbreaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919(WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, an immuno-oncology agent is an OX40 agonist. Insome embodiments, an OX40 agonist is an agonistic OX40 antibody. In someembodiments, an OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, an immuno-oncology agent is an OX40L antagonist. Insome embodiments, an OX40L antagonist is an antagonistic OX40 antibody.In some embodiments, an OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, an immuno-oncology agent is a CD40 agonist. In someembodiments, a CD40 agonist is an agonistic CD40 antibody. In someembodiments, an immuno-oncology agent is a CD40 antagonist. In someembodiments, a CD40 antagonist is an antagonistic CD40 antibody. In someembodiments, a CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, an immuno-oncology agent is a CD27 agonist. In someembodiments, a CD27 agonist is an agonistic CD27 antibody. In someembodiments, a CD27 antibody is varlilumab.

In some embodiments, an immuno-oncology agent is MGA271 (to B7H3)(WO11/109400).

In some embodiments, an immuno-oncology agent is abagovomab,adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab,atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab,epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab,ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab,obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab,pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, an immuno-oncology agent is an immunostimulatoryagent. For example, antibodies blocking the PD-1 and PD-L1 inhibitoryaxis can unleash activated tumor-reactive T cells and have been shown inclinical trials to induce durable anti-tumor responses in increasingnumbers of tumor histologies, including some tumor types thatconventionally have not been considered immunotherapy sensitive. See,e.g., Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al.(2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®,Bristol-Myers Squibb, also known as ONO-4538, MDX1106 and BMS-936558),has shown potential to improve the overall survival in patients with RCCwho had experienced disease progression during or after prioranti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic specificallyinduces apoptosis of tumor cells. Approved immunomodulatory therapeuticswhich may be used in the present invention include pomalidomide(Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenolmebutate (Picato®, LEO Pharma).

In some embodiments, an immuno-oncology agent is a cancer vaccine. Insome embodiments, the cancer vaccine is selected from sipuleucel-T(Provenge®, Dendreon/Valeant Pharmaceuticals), which has been approvedfor treatment of asymptomatic, or minimally symptomatic metastaticcastrate-resistant (hormone-refractory) prostate cancer; and talimogenelaherparepvec (Imlygic®, BioVex/Amgen, previously known as T-VEC), agenetically modified oncolytic viral therapy approved for treatment ofunresectable cutaneous, subcutaneous and nodal lesions in melanoma. Insome embodiments, an immuno-oncology agent is selected from an oncolyticviral therapy such as pexastimogene devacirepvec (PexaVec/JX-594,SillaJen/formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)deficient vaccinia virus engineered to express GM-CSF, forhepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312);pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratoryenteric orphan virus (reovirus) which does not replicate in cells thatare not RAS-activated, in numerous cancers, including colorectal cancer(NCT01622543); prostate cancer (NCT01619813); head and neck squamouscell cancer (NCT01166542); pancreatic adenocarcinoma (NCT00998322); andnon-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev(NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineeredto express a full length CD80 and an antibody fragment specific for theT-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastaticor advanced epithelial tumors such as in colorectal cancer, bladdercancer, head and neck squamous cell carcinoma and salivary gland cancer(NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirusengineered to express GM-CSF, in melanoma (NCT03003676); and peritonealdisease, colorectal cancer or ovarian cancer (NCT02963831); GL-ONC1(GLV-1 h68/GLV-1 h153, Genelux GmbH), vaccinia viruses engineered toexpress beta-galactosidase (beta-gal)/beta-glucoronidase orbeta-gal/human sodium iodide symporter (hNIS), respectively, werestudied in peritoneal carcinomatosis (NCT01443260); fallopian tubecancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), anadenovirus engineered to express GM-CSF, in bladder cancer(NCT02365818).

In some embodiments, an immuno-oncology agent is selected from JX-929(SillaJen/formerly Jennerex Biotherapeutics), a TK- and vaccinia growthfactor-deficient vaccinia virus engineered to express cytosinedeaminase, which is able to convert the prodrug 5-fluorocytosine to thecytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax/formerly Oncos),peptide-based immunotherapy agents targeted for difficult-to-treat RASmutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirusdesignated: Ad5/3-E2F-delta24-hTNFa-IRES-hIL20; and VSV-GP(ViraTherapeutics) a vesicular stomatitis virus (VSV) engineered toexpress the glycoprotein (GP) of lymphocytic choriomeningitis virus(LCMV), which can be further engineered to express antigens designed toraise an antigen-specific CD8⁺ T cell response.

In some embodiments, an immuno-oncology agent is a T-cell engineered toexpress a chimeric antigen receptor, or CAR. The T-cells engineered toexpress such chimeric antigen receptor are referred to as a CAR-T cells.

CARs have been constructed that consist of binding domains, which may bederived from natural ligands, single chain variable fragments (scFv)derived from monoclonal antibodies specific for cell-surface antigens,fused to endodomains that are the functional end of the T-cell receptor(TCR), such as the CD3-zeta signaling domain from TCRs, which is capableof generating an activation signal in T lymphocytes. Upon antigenbinding, such CARs link to endogenous signaling pathways in the effectorcell and generate activating signals similar to those initiated by theTCR complex.

For example, in some embodiments the CAR-T cell is one of thosedescribed in U.S. Pat. No. 8,906,682 (June; hereby incorporated byreference in its entirety), which discloses CAR-T cells engineered tocomprise an extracellular domain having an antigen binding domain (suchas a domain that binds to CD19), fused to an intracellular signalingdomain of the T cell antigen receptor complex zeta chain (such as CD3zeta). When expressed in the T cell, the CAR is able to redirect antigenrecognition based on the antigen binding specificity. In the case ofCD19, the antigen is expressed on malignant B cells. Over 200 clinicaltrials are currently in progress employing CAR-T in a wide range ofindications.[https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, an immunostimulatory agent is an activator ofretinoic acid receptor-related orphan receptor γ (RORγt). RORγt is atranscription factor with key roles in the differentiation andmaintenance of Type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) Tcells, as well as the differentiation of IL-17 expressing innate immunecell subpopulations such as NK cells. In some embodiments, an activatorof RORγt is LYC-55716 (Lycera), which is currently being evaluated inclinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, an immunostimulatory agent is an agonist oractivator of a toll-like receptor (TLR). Suitable activators of TLRsinclude an agonist or activator of TLR9 such as SD-101 (Dynavax). SD-101is an immunostimulatory CpG which is being studied for B-cell,follicular and other lymphomas (NCT02254772). Agonists or activators ofTLR8 which may be used in the present invention include motolimod(VTX-2337, VentiRx Pharmaceuticals) which is being studied for squamouscell cancer of the head and neck (NCT02124850) and ovarian cancer(NCT02431559).

Other immuno-oncology agents that may be used in the present inventioninclude urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), ananti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), ananti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody;monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2Amonoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), ananti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonalantibody.

In some embodiments, an immunostimulatory agent is selected fromelotuzumab, mifamurtide, an agonist or activator of a toll-likereceptor, and an activator of RORγt.

In some embodiments, an immunostimulatory therapeutic is recombinanthuman interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic asa therapy for melanoma and renal cell carcinoma (NCT01021059 andNCT01369888) and leukemias (NCT02689453). In some embodiments, animmunostimulatory agent is recombinant human interleukin 12 (rhIL-12).In some embodiments, an IL-15 based immunotherapeutic is heterodimericIL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of asynthetic form of endogenous IL-15 complexed to the soluble IL-15binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which hasbeen tested in Phase 1 clinical trials for melanoma, renal cellcarcinoma, non-small cell lung cancer and head and neck squamous cellcarcinoma (NCT02452268). In some embodiments, a recombinant humaninterleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724,or NCT02542124.

In some embodiments, an immuno-oncology agent is selected from thosedescripted in Jerry L. Adams ET. AL., “Big opportunities for smallmolecules in immuno-oncology,” Cancer Therapy 2015, Vol. 14, pages603-622, the content of which is incorporated herein by reference in itsentirety. In some embodiment, an immuno-oncology agent is selected fromthe examples described in Table 1 of Jerry L. Adams ET. AL. In someembodiments, an immuno-oncology agent is a small molecule targeting animmuno-oncoloby target selected from those listed in Table 2 of Jerry L.Adams ET. AL. In some embodiments, an immuno-oncology agent is a smallmolecule agent selected from those listed in Table 2 of Jerry L. AdamsET. AL.

In some embodiments, an immuno-oncology agent is selected from the smallmolecule immuno-oncology agents described in Peter L. Toogood, “Smallmolecule immuno-oncology therapeutic agents,” Bioorganic & MedicinalChemistry Letters 2018, Vol. 28, pages 319-329, the content of which isincorporated herein by reference in its entirety. In some embodiments,an immuno-oncology agent is an agent targeting the pathways as describedin Peter L. Toogood.

In some embodiments, an immuno-oncology agent is selected from thosedescribed in Sandra L. Ross et al., “Bispecific T cell engager (BiTE®)antibody constructs can mediate bystander tumor cell killing”, PLoS ONE12(8): e0183390, the content of which is incorporated herein byreference in its entirety. In some embodiments, an immuno-oncology agentis a bispecific T cell engager (BiTE®) antibody construct. In someembodiments, a bispecific T cell engager (BiTE®) antibody construct is aCD19/CD3 bispecific antibody construct. In some embodiments, abispecific T cell engager (BiTE®) antibody construct is an EGFR/CD3bispecific antibody construct. In some embodiments, a bispecific T cellengager (BiTE®) antibody construct activates T cells. In someembodiments, a bispecific T cell engager (BiTE®) antibody constructactivates T cells, which release cytokines inducing upregulation ofintercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells.In some embodiments, a bispecific T cell engager (BiTE®) antibodyconstruct activates T cells which result in induced bystander celllysis. In some embodiments, the bystander cells are in solid tumors. Insome embodiments, the bystander cells being lysed are in proximity tothe BiTE®-activated T cells. In some embodiment, the bystander cellscomprises tumor-associated antigen (TAA) negative cancer cells. In someembodiment, the bystander cells comprise EGFR-negative cancer cells. Insome embodiments, an immuno-oncology agent is an antibody which blocksthe PD-L1/PD1 axis and/or CTLA4. In some embodiments, an immuno-oncologyagent is an ex-vivo expanded tumor-infiltrating T cell. In someembodiments, an immuno-oncology agent is a bispecific antibody constructor chimeric antigen receptors (CARs) that directly connect T cells withtumor-associated surface antigens (TAAs).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, an immuno-oncology agent is an immune checkpointinhibitor as described herein.

The term “checkpoint inhibitor” as used herein relates to agents usefulin preventing cancer cells from avoiding the immune system of thepatient. One of the major mechanisms of anti-tumor immunity subversionis known as “T-cell exhaustion,” which results from chronic exposure toantigens that has led to up-regulation of inhibitory receptors. Theseinhibitory receptors serve as immune checkpoints in order to preventuncontrolled immune reactions.

PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T cellImmunoglobulin and Mucin domain-3 (Tim-3), Lymphocyte Activation Gene-3(Lag-3; CD223), and others are often referred to as a checkpointregulators. They act as molecular “gatekeepers” that allow extracellularinformation to dictate whether cell cycle progression and otherintracellular signaling processes should proceed.

In some embodiments, an immune checkpoint inhibitor is an antibody toPD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) toprevent the receptor from binding to the inhibitory ligand PDL-1, thusoverriding the ability of tumors to suppress the host anti-tumor immuneresponse.

In one aspect, the checkpoint inhibitor is a biologic therapeutic or asmall molecule. In another aspect, the checkpoint inhibitor is amonoclonal antibody, a humanized antibody, a fully human antibody, afusion protein or a combination thereof. In a further aspect, thecheckpoint inhibitor inhibits a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an additional aspect, the checkpoint inhibitorinteracts with a ligand of a checkpoint protein selected from CTLA-4,PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR,2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or acombination thereof. In an aspect, the checkpoint inhibitor is animmunostimulatory agent, a T cell growth factor, an interleukin, anantibody, a vaccine or a combination thereof. In a further aspect, theinterleukin is IL-7 or IL-15. In a specific aspect, the interleukin isglycosylated IL-7. In an additional aspect, the vaccine is a dendriticcell (DC) vaccine.

Checkpoint inhibitors include any agent that blocks or inhibits in astatistically significant manner, the inhibitory pathways of the immunesystem. Such inhibitors may include small molecule inhibitors or mayinclude antibodies, or antigen binding fragments thereof, that bind toand block or inhibit immune checkpoint receptors or antibodies that bindto and block or inhibit immune checkpoint receptor ligands. Illustrativecheckpoint molecules that may be targeted for blocking or inhibitioninclude, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4,BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belongs to the CD2 familyof molecules and is expressed on all NK, γδ, and memory CD8⁺ (αβ) Tcells), CD160 (also referred to as BY55), CGEN-15049, CHK 1 and CHK2kinases, A2aR, and various B-7 family ligands. B7 family ligandsinclude, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3,B7-H4, B7-H5, B7-H6 and B7-H7. Checkpoint inhibitors include antibodies,or antigen binding fragments thereof, other binding proteins, biologictherapeutics, or small molecules, that bind to and block or inhibit theactivity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3,GAL9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immunecheckpoint inhibitors include Tremelimumab (CTLA-4 blocking antibody),anti-OX40, PD-L1 monoclonal Antibody (Anti-B7-H1; MED14736), MK-3475(PD-1 blocker), Nivolumab (anti-PD1 antibody), CT-011 (anti-PD1antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody),BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody),MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpointinhibitor). Checkpoint protein ligands include, but are not limited toPD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected froma PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In someembodiments, the checkpoint inhibitor is selected from the groupconsisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), andpembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitoris selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-MyersSquibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck);ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb);durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); andatezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the groupconsisting of lambrolizumab (MK-3475), nivolumab (BMS-936558),pidilizumab (CT-Oll), AMP-224, MDX-1105, MEDI4736, MPDL3280A,BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®),and tremelimumab.

In some embodiments, an immune checkpoint inhibitor is REGN2810(Regeneron), an anti-PD-1 antibody tested in patients with basal cellcarcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cellcarcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma(NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibodythat binds to PD-1, in clinical trials for diffuse large B-cell lymphomaand multiple myeloma; avelumab (Bavencio®, Pfizer/Merck KGaA), alsoknown as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody, inclinical trials for non-small cell lung cancer, Merkel cell carcinoma,mesothelioma, solid tumors, renal cancer, ovarian cancer, bladdercancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis),an inhibitory antibody that binds to PD-1, in clinical trials fornon-small cell lung cancer, melanoma, triple negative breast cancer andadvanced or metastatic solid tumors. Tremelimumab (CP-675,206;Astrazeneca) is a fully human monoclonal antibody against CTLA-4 thathas been in studied in clinical trials for a number of indications,including: mesothelioma, colorectal cancer, kidney cancer, breastcancer, lung cancer and non-small cell lung cancer, pancreatic ductaladenocarcinoma, pancreatic cancer, germ cell cancer, squamous cellcancer of the head and neck, hepatocellular carcinoma, prostate cancer,endometrial cancer, metastatic cancer in the liver, liver cancer, largeB-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplasticthyroid cancer, urothelial cancer, fallopian tube cancer, multiplemyeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884(Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1clinical trials for advanced solid tumors (NCT02694822).

In some embodiments, a checkpoint inhibitor is an inhibitor of T-cellimmunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors thatmay be used in the present invention include TSR-022, LY3321367 andMBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody which is beingstudied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is ananti-TIM-3 antibody which is being studied in solid tumors(NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody which isbeing studied in advanced malignancies (NCT02608268).

In some embodiments, a checkpoint inhibitor is an inhibitor of T cellimmunoreceptor with Ig and ITIM domains, or TIGIT, an immune receptor oncertain T cells and NK cells. TIGIT inhibitors that may be used in thepresent invention include BMS-986207 (Bristol-Myers Squibb), ananti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); andanti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, a checkpoint inhibitor is an inhibitor ofLymphocyte Activation Gene-3 (LAG-3). LAG-3 inhibitors that may be usedin the present invention include BMS-986016 and REGN3767 and IMP321.BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is beingstudied in glioblastoma and gliosarcoma (NCT02658981). REGN3767(Regeneron), is also an anti-LAG-3 antibody, and is being studied inmalignancies (NCT03005782). IMP321 (Immutep S.A.) is an LAG-3-Ig fusionprotein, being studied in melanoma (NCT02676869); adenocarcinoma(NCT02614833); and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that may be used in the present invention includeOX40 agonists. OX40 agonists that are being studied in clinical trialsinclude PF-04518600/PF-8600 (Pfizer), an agonistic anti-OX40 antibody,in metastatic kidney cancer (NCT03092856) and advanced cancers andneoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonisticanti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562(Medimmune/AstraZeneca), an agonistic anti-OX40 antibody, in advancedsolid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonisticanti-OX40 antibody (Medimmune/AstraZeneca), in patients with colorectalcancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer(NCT02274155) and metastatic prostate cancer (NCT01303705); andBMS-986178 (Bristol-Myers Squibb) an agonistic anti-OX40 antibody, inadvanced cancers (NCT02737475).

Checkpoint inhibitors that may be used in the present invention includeCD137 (also called 4-1BB) agonists. CD137 agonists that are beingstudied in clinical trials include utomilumab (PF-05082566, Pfizer) anagonistic anti-CD137 antibody, in diffuse large B-cell lymphoma(NCT02951156) and in advanced cancers and neoplasms (NCT02554812 andNCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonisticanti-CD137 antibody, in melanoma and skin cancer (NCT02652455) andglioblastoma and gliosarcoma (NCT02658981).

Checkpoint inhibitors that may be used in the present invention includeCD27 agonists. CD27 agonists that are being studied in clinical trialsinclude varlilumab (CDX-1127, Celldex Therapeutics) an agonisticanti-CD27 antibody, in squamous cell head and neck cancer, ovariancarcinoma, colorectal cancer, renal cell cancer, and glioblastoma(NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma(NCT02924038).

Checkpoint inhibitors that may be used in the present invention includeglucocorticoid-induced tumor necrosis factor receptor (GITR) agonists.GITR agonists that are being studied in clinical trials include TRX518(Leap Therapeutics), an agonistic anti-GITR antibody, in malignantmelanoma and other malignant solid tumors (NCT01239134 and NCT02628574);GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors andlymphoma (NCT 02740270); INCAGNO1876 (Incyte/Agenus), an agonisticanti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110);MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors(NCT02132754) and MEDI1873 (Medimmune/AstraZeneca), an agonistichexameric GITR-ligand molecule with a human IgG1 Fc domain, in advancedsolid tumors (NCT02583165).

Checkpoint inhibitors that may be used in the present invention includeinducible T-cell co-stimulator (ICOS, also known as CD278) agonists.ICOS agonists that are being studied in clinical trials include MEDI-570(Medimmune), an agonistic anti-ICOS antibody, in lymphomas(NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody, inPhase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonisticanti-ICOS antibody, in Phase 1 (NCT02904226).

Checkpoint inhibitors that may be used in the present invention includekiller IgG-like receptor (KIR) inhibitors. KIR inhibitors that are beingstudied in clinical trials include lirilumab (IPH2102/BMS-986015, InnatePharma/Bristol-Myers Squibb), an anti-KIR antibody, in leukemias(NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma(NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (InnatePharma), an anti-KIR antibody that binds to three domains of the longcytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

Checkpoint inhibitors that may be used in the present invention includeCD47 inhibitors of interaction between CD47 and signal regulatoryprotein alpha (SIRPa). CD47/SIRPa inhibitors that are being studied inclinical trials include ALX-148 (Alexo Therapeutics), an antagonisticvariant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediatedsignaling, in phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, TrilliumTherapeutics), a soluble recombinant fusion protein created by linkingthe N-terminal CD47-binding domain of SIRPa with the Fc domain of humanIgG1, acts by binding human CD47, and preventing it from delivering its“do not eat” signal to macrophages, is in clinical trials in Phase 1(NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47antibody, in leukemias (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.),in colorectal neoplasms and solid tumors (NCT02953782), acute myeloidleukemia (NCT02678338) and lymphoma (NCT02953509).

Checkpoint inhibitors that may be used in the present invention includeCD73 inhibitors. CD73 inhibitors that are being studied in clinicaltrials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solidtumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), ananti-CD73 antibody, in solid tumors (NCT02754141).

Checkpoint inhibitors that may be used in the present invention includeagonists of stimulator of interferon genes protein (STING, also known astransmembrane protein 173, or TMEM173). Agonists of STING that are beingstudied in clinical trials include MK-1454 (Merck), an agonisticsynthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100(MIW815, Aduro Biotech/Novartis), an agonistic synthetic cyclicdinucleotide, in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that may be used in the present invention includeCSF1R inhibitors. CSF1R inhibitors that are being studied in clinicaltrials include pexidartinib (PLX3397, Plexxikon), a CSF1R small moleculeinhibitor, in colorectal cancer, pancreatic cancer, metastatic andadvanced cancers (NCT02777710) and melanoma, non-small cell lung cancer,squamous cell head and neck cancer, gastrointestinal stromal tumor(GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly),an anti-CSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma(NCT03101254), and solid tumors (NCT02718911); and BLZ945(4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylicacid methylamide, Novartis), an orally available inhibitor of CSF1R, inadvanced solid tumors (NCT02829723).

Checkpoint inhibitors that may be used in the present invention includeNKG2A receptor inhibitors. NKG2A receptor inhibitors that are beingstudied in clinical trials include monalizumab (IPH2201, Innate Pharma),an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) andchronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected fromnivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab,atezolizumab, or pidilizumab.

EXEMPLIFICATION Abbreviations

-   -   Ac: acetyl    -   AcOH: acetic acid    -   ACN: acetonitrile    -   Ad: adamantly    -   AIBN: 2,2′-azo bisisobutyronitrile    -   Anhyd: anhydrous    -   Aq: aqueous    -   B₂Pin₂: bis        (pinacolato)diboron-4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)    -   BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl    -   BH₃: Borane    -   Bn: benzyl    -   Boc: tert-butoxycarbonyl    -   Boc₂O: di-tert-butyl dicarbonate    -   BPO: benzoyl peroxide    -   ^(n)BuOH: n-butanol    -   CDI: carbonyldiimidazole    -   COD: cyclooctadiene    -   d: days    -   DABCO: 1,4-diazobicyclo[2.2.2]octane    -   DAST: diethylaminosulfur trifluoride    -   dba: dibenzylideneacetone    -   DBU: 1,8-diazobicyclo[5.4.0]undec-7-ene    -   DCE: 1,2-dichloroethane    -   DCM: dichloromethane    -   DEA: diethylamine    -   DHP: dihydropyran    -   DIBAL-H: diisobutylaluminum hydride    -   DIPA: diisopropylamine    -   DIPEA or DIEA: N,N-diisopropylethylamine    -   DMA: N,N-dimethylacetamide    -   DME: 1,2-dimethoxyethane    -   DMAP: 4-dimethylaminopyridine    -   DMF: N,N-dimethylformamide    -   DMP: Dess-Martin periodinane    -   DMSO-dimethyl sulfoxide    -   DPPA: diphenylphosphoryl azide    -   dppf: 1,1′-bis(diphenylphosphino)ferrocene    -   EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide        hydrochloride    -   ee: enantiomeric excess    -   ESI: electrospray ionization    -   EA: ethyl acetate    -   EtOAc: ethyl acetate    -   EtOH: ethanol    -   FA: formic acid    -   h or hrs: hours    -   HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium        hexafluorophosphate    -   HCl: hydrochloric acid    -   HPLC: high performance liquid chromatography    -   HOAc: acetic acid    -   IBX: 2-iodoxybenzoic acid    -   IPA: isopropyl alcohol    -   KHMDS: potassium hexamethyldisilazide    -   K₂CO₃: potassium carbonate    -   LAH: lithium aluminum hydride    -   LDA: lithium diisopropylamide    -   m-CPBA: meta-chloroperbenzoic acid    -   M: molar    -   MeCN: acetonitrile    -   MeOH: methanol    -   Me₂S: dimethyl sulfide    -   MeONa: sodium methylate    -   MeI: iodomethane    -   min: minutes    -   mL: milliliters    -   mM: millimolar    -   mmol: millimoles    -   MPa: mega pascal    -   MOMCl: methyl chloromethyl ether    -   MsCl: methanesulfonyl chloride    -   MTBE: methyl tert-butyl ether    -   nBuLi: n-butyllithium    -   NaNO₂: sodium nitrite    -   NaOH: sodium hydroxide    -   Na₂SO₄: sodium sulfate    -   NBS: N-bromosuccinimide    -   NCS: N-chlorosuccinimide    -   NFSI: N-Fluorobenzenesulfonimide    -   NMO: N-methylmorpholine N-oxide    -   NMP: N-methylpyrrolidine    -   NMR: Nuclear Magnetic Resonance    -   ° C.: degrees Celsius    -   Pd/C: Palladium on Carbon    -   Pd(OAc)₂: Palladium Acetate    -   PBS: phosphate buffered saline    -   PE: petroleum ether    -   POCl₃: phosphorus oxychloride    -   PPh₃: triphenylphosphine    -   PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium        hexafluorophosphate    -   Rel: relative    -   R.T. or rt: room temperature    -   sat: saturated    -   SEMCl: chloromethyl-2-trimethylsilylethyl ether    -   SFC: supercritical fluid chromatography    -   SOCl₂: sulfur dichloride    -   tBuOK: potassium tert-butoxide    -   TBAB: tetrabutylammonium bromide    -   TBAI: tetrabutylammonium iodide    -   TEA: triethylamine    -   Tf: trifluoromethanesulfonate    -   TfAA, TFMSA or Tf₂O: trifluoromethanesulfonic anhydride    -   TFA: trifluoracetic acid    -   TIPS: triisopropylsilyl    -   THF: tetrahydrofuran    -   THP: tetrahydropyran    -   TLC: thin layer chromatography    -   TMEDA: tetramethylethylenediamine    -   pTSA: para-toluenesulfonic acid    -   wt: weight    -   Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, preferably between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

All reactions are carried out under nitrogen or argon unless otherwisestated.

Proton NMR (¹H NMR) is conducted in deuterated solvent. In certaincompounds disclosed herein, one or more ¹H shifts overlap with residualproteo solvent signals; these signals have not been reported in theexperimental provided hereinafter.

TABLE 2 Analytical instruments LCMS Shimadzu UFLC MS: LCMS-2020 AgilentTechnologies 1200 series MS: Agilent Technologies 6110 AgilentTechnologies 1200 series MS: LC/MSD VL NMR BRUKER AVANCE III/400;Frequency (MHz) 400.13; Nucleus: 1H; Number of Transients: 8 Prep-HPLCGilson GX-281 systems: instruments GX-A, GX-B, GX-C, GX-D, GX-E, GX-F,GX-G and GX-H GCMS SHIMADZU GCMS-QP2010 Ultra Analytical cSFC AgilentTechnologies 1290 Infinity Prep-cSFC Waters SFC Prep 80

For Acidic LCMS Data:

LCMS was recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS2020equipped with electro-spray ionization and quadruple MS detector [ES+veto give MH⁺] and equipped with Chromolith Flash RP-18e 25*2.0 mm,eluting with 0.0375 vol % TFA in water (solvent A) and 0.01875 vol % TFAin acetonitrile (solvent B). Other LCMS was recorded on an Agilent 1290Infinity RRLC attached with Agilent 6120 Mass detector. The column usedwas BEH C18 50*2.1 mm, 1.7 micron. Column flow was 0.55 ml/min andmobile phase were used (A) 2 mM Ammonium Acetate in 0.10% Formic Acid inWater and (B) 0.1% Formic Acid in Acetonitrile.

For Basic LCMS Data:

LCMS was recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS 2020equipped with electro-spray ionization and quadruple ms detector [es+veto give mh⁺] and equipped with xbridge C18, 2.1×50 mm columns packedwith 5 mm C18-coated silica or Kinetex EVO C18 2.1×30 mm columns packedwith 5 mm C18-coated silica, eluting with 0.05 vol % NH₃—H₂O in water(solvent A) and acetonitrile (solvent B).

HPLC Analytical Method:

HPLC was carried out on X Bridge C18 150*4.6 mm, 5 micron. Column flowwas 1.0 ml/min and mobile phase were used (A) 0.1% Ammonia in water and(B) 0.1% Ammonia in Acetonitrile.

Prep HPLC Analytical Method:

The compound was purified on Shimadzu LC-20AP and UV detector. Thecolumn used was X-BRIDGE C18 (250*19) mm, 5p. Column flow was 16.0ml/min. Mobile phase were used (A) 0.1% Formic Acid in Water and (B)Acetonitrile Basic method used (A) 5 mM ammonium bicarbonate and 0.1%NH3 in Water and (B) Acetonitrile or (A) 0.1% Ammonium Hydroxide inWater and (B) Acetonitrile. The UV spectra were recorded at 202 nm & 254nm.

NMR Method:

The 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400MHz/5 mm Probe (BBFO). The chemical shifts are reported inpart-per-million.

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

INTERMEDIATES 1-azido-5-bromopentane (Intermediate A)

To a stirred solution of sodium azide (2.5 g, 38.5 mmol) in DMF (85 mL)was added 1,5-dibromopentane (8.4 g, 36.7 mmol) at room temperature. Theresulting reaction mixture was then stirred at 50° C. for 16 h. Thereaction mixture was transferred into ice water and the resultingmixture was extracted using ethyl acetate (3×100 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated under reduced pressure to give1-azido-5-bromopentane as colorless oil (5.0 g, 71%). ¹H NMR (400 MHz,DMSO) δ 3.44 (t, J=6.8 Hz, 2H), 3.32 (t, J=4 Hz, 2H), 1.95-1.91 (m, 2H),1.67-1.62 (m, 2H), 1.56-1.46 (m, 2H).

Tert-Butyl (5-(2-(2-((5-aminopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate(Intermediate B)

Step 1—tert-butyl (5-hydroxypentyl)carbamate

To a stirred solution of 5-aminopentan-1-ol (10.0 g, 96.9 mmol) in DCM(75 mL) was added Boc-anhydride (25.4 g, 116.3 mmol) dropwise at 0° C.The resulting reaction mixture was allowed to warm to room temperatureand stirred at rt for 1 h. The reaction mixture was transferred into icewater and the resulting mixture was extracted using DCM (3×100 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to givetert-butyl (5-hydroxypentyl)carbamate as colorless oil (16 g, 81%). ¹HNMR (400 MHz, DMSO) δ 4.56 (bs, 1H), 3.69-3.64 (m, 2H), 3.17-3.12 (m,2H), 1.64-1.62 (m, 2H), 1.54-1.53 (m, 6H), 1.51-1.49 (m, 1H), 1.46 (s,9H), 1.43-1.37 (m, 2H).

Step 2—5-((tert-butoxycarbonyl)amino)pentyl methanesulfonate

To a stirred solution of tert-butyl (5-hydroxypentyl)carbamate (6.0 g,29.5 mmol) and triethylamine (13 mL, 88.5 mmol) in DCM (100 mL) wasadded mesyl chloride (3.7 mL, 44.3 mmol) dropwise at 0° C. The resultingreaction mixture was allowed to warm to room temperature and stirred atrt for 2 h. The reaction mixture was transferred into water and theresulting mixture was extracted using DCM (3×100 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated under reduced pressure to give5-((tert-butoxycarbonyl)amino)pentyl methanesulfonate as white solid(7.0 g, 84%). LCMS: (ES⁺) m/z (M+H)⁺

Step 3—Tert-Butyl (5-(2-(2-(benzyloxy)ethoxy)ethoxy)pentyl)carbamate

To a stirred solution of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (3.3 g, 16.8mmol, CAS #2050-25-1) and 5-((tert-butoxycarbonyl)amino)pentylmethanesulfonate (7.0 g, 25.2 mmol) in toluene (50 mL) and 8 N AqueousNaOH solution (50 mL) was added TBAB (catalytic amount) at roomtemperature. The resulting reaction mixture was allowed to stir at 80°C. for 16 h. The reaction mixture was then transferred into ice waterand the resulting mixture was extracted using ethyl acetate (3×100 mL).The combined organic layers were dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to affordthe crude product. The crude product was purified using silica gelcolumn chromatography (25% EtOAc-Hexanes) to give tert-butyl(5-(2-(2-(benzyloxy)ethoxy)ethoxy)pentyl)carbamate as colorless oil (3.5g, 55%). ¹H NMR (400 MHz, DMSO) δ 7.36 (d, J=4.4 Hz, 2H), 7.32-7.28 (m,2H), 4.59 (s, 1H), 3.71-3.70 (m, 2H), 3.69-3.67 (m, 1H), 3.66-3.65 (m,1H), 3.13-3.11 (m, 1H), 1.65-1.61 (m, 2H), 1.59-1.54 (m, 6H), 1.50-1.48(m, 1H).

Step 4—Tert-Butyl (5-(2-(2-hydroxyethoxy)ethoxy)pentyl)carbamate

To a stirred solution of tert-butyl(5-(2-(2-(benzyloxy)ethoxy)ethoxy)pentyl)carbamate (3.5 g, 9.2 mmol) inethanol (30 mL), THF (30 mL), ethyl acetate (30 mL) and acetic acid (2mL) was added 20% Pd(OH)₂ (2.5 g) at room temperature under nitrogenatmosphere. The resulting reaction mixture was allowed to stir underhydrogen gas (20 kg/cm² pressure) in an autoclave at 60° C. for 16 h.The reaction mixture was filtered through celite with a vacuum andwashed with MeOH (50 mL). The filtrate was evaporated under reducedpressure to give tert-butyl(5-(2-(2-hydroxyethoxy)ethoxy)pentyl)carbamate as colorless oil (2.5 g,93%). ¹H NMR (400 MHz, DMSO) δ 4.68 (bs, 1H), 3.77-3.75 (m, 2H), (s,1H), 3.71-3.69 (m, 2H), 3.69-3.64 (m, 2H), 3.63-3.59 (m, 2H), 3.51-3.48(m, 2H), 3.14-3.13 (m, 3H), 1.71-1.61 (m, 2H), 1.59-1.55 (m, 2H), 1.45(s, 9H), 1.42-1.36 (m, 2H).

Step 5—Tert-Butyl(5-(2-(2-((5-azidopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate

To a stirred solution of tert-butyl(5-(2-(2-hydroxyethoxy)ethoxy)pentyl)carbamate (1.4 g, 4.8 mmol) and1-azido-5-bromopentane (2.8 g, 14.4 mmol, Intermediate A) in toluene (10mL) and 8 N aqueous NaOH solution (10 mL) was added TBAB (catalyticamount) at rt. The resulting reaction mixture was then heated to 80° C.and stirred for 16 h. The reaction mixture was transferred into icewater and the resulting mixture was extracted using ethyl acetate (3×100mL). The combined organic layers were dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureto give tert-butyl(5-(2-(2-((5-azidopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate as colorlessoil (0.95 g, 50%). ¹H NMR (400 MHz, DMSO) δ 4.56 (bs, 1H), 3.69-3.61 (m,4H), 3.50-3.46 (m, 3H), 3.33-3.27 (m, 1H), 3.14-3.12 (m, 1H), 1.68-1.61(m, 4H), 1.53-1.42 (m, 7H).

Step 6—Tert-Butyl (5-(2-(2-hydroxyethoxy)ethoxy)pentyl)carbamate

To a stirred solution of tert-butyl(5-(2-(2-((5-azidopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate (0.45 g,1.12 mmol) in methanol (30 mL) was added 20% Pd(OH)₂ (0.45 g) at roomtemperature under nitrogen atmosphere. The resulting reaction mixturewas stirred under hydrogen gas (20 kg/cm2 pressure) in an auto clave atrt for 3 h. The reaction mixture was filtered through a pad of celiteunder vacuum and washed with MeOH (50 mL). The filtrate was evaporatedunder reduced pressure to give tert-butyl(5-(2-(2-((5-aminopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate as colorlessoil (0.35 g, 83%).

(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicAcid (Intermediate C)

Step 1: Methyl(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylate

To a stirred solution of6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinic acid(1.85 g, 5.76 mmol, Intermediate N) and methyl(1R,4R)-4-aminocyclohexane-1-carboxylate hydrochloride (1.34 g, 6.91mmol) in DMF (10 mL) was added DIPEA (5 mL, 28.8 mmol) and PyBOP (4.5 g,8.64 mmol) at rt. The resulting reaction mixture was stirred at rt for16 h. The reaction mixture was then transferred into ice water and theresulting precipitate was filtered off, and dried reduced pressure. Thecrude product was purified using silica gel column chromatography (7%MeOH-DCM) to give methyl(1r,4r)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylateas light a green solid (1.3 g, 49%). LC-MS (ESI+) m/z 460.54 (M+H)+

Step2—(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicAcid

To a stirred solution of methyl(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylate(1.2 g, 2.6 mmol) in MeOH (20 mL) was added NaOH (2 g, 50 mmol) in 20 mLwater dropwise at rt. The resulting reaction mixture was stirred at rtfor 3 h. The reaction mixture was then evaporated under vacuum, water(10 mL) was added and pH was adjusted to 6-7 using 10% citric acidsolution. The resulting mixture was stirred for 15 min, the solidprecipitate was filtered off and dried under vacuum to give(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicacid as a brown solid (0.9 g, 77%). LC-MS (ESI+) m/z 446.51 (M+H)+

2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid(Intermediate D)

Step 1—Tert-Butyl (2,6-dioxopiperidin-3-yl)carbamate

To a stirred solution of (tert-butoxycarbonyl)-L-glutamine (6.0 g, 24mmol) in THF (60 mL) was added CDI (4.2 g, 25.9 mmol) and DMAP (0.012 g,0.098 mmol) at rt. The resulting reaction mixture heated to 70° C. andstirred for 16 h. The reaction precipitate was filtered and washed withTHF (50 mL), and dried under reduced pressure to give tert-butyl(2,6-dioxopiperidin-3-yl)carbamate as white solid (1.8 g, 32%). LCMS(ESI⁻) m/z 227.2 (M−H)⁻.

Step 2—3-aminopiperidine-2,6-dione (TFA Salt)

tert-Butyl (2,6-dioxopiperidin-3-yl)carbamate (1.8 g, 7.9 mmol) wasdissolved in TFA (10 mL) and stirred at rt for 1 h. The reaction mixturewas then evaporated under reduced pressure to give3-aminopiperidine-2,6-dione as the TFA salt as a brown solid (1.7 g,96%). LCMS (ESI⁺) m/z 129 (M+H)⁺.

Step 3—2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione

To a stirred solution of 4-hydroxyisobenzofuran-1,3-dione (1.2 g, 7.3mmol) in pyridine (25 mL) was added 3-aminopiperidine-2,6-dione-TFA salt(1.8 g, 7.3 mmol) at room temperature. The resulting reaction mixturewas then warmed to 110° C. and stirred for 16 h. The reaction mixturewas then evaporated under reduced pressure. The crude product waspurified using silica gel column chromatography (4% MeOH-DCM) to give2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione as yellowsolid (1 g, 50%). LC-MS (ESI⁻) m/z 273.2 (M−H)⁺.

Step 4—Tert-Butyl2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindoline-1,3-dione (2.95 g,10.76 mmol) and K₂CO₃ (2.22 g, 16.14 mmol) in DMF (40 mL) was addedtert-butyl 2-bromoacetate (1.6 mL, 10.16 mmol) in DMF (10 mL) dropwiseat rt. The resulting reaction mixture was stirred at rt for 2 h. Thereaction mixture was then transferred into ice water and the resultingmixture was extracted using ethyl acetate (3×100 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated under reduced pressure and the crude productwas purified using silica gel column chromatography (50% EAc-Hexanes) togive tert-butyl2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate aswhite solid (3 g, 72%). LC-MS (ESI⁻) m/z 387.2 (M−H)⁺.

Step5—2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)aceticAcid

tert-Butyl2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetate(3.0 g, 7.7 mmol) was dissolved in TFA (30 mL) and stirred at rt for 1h. The reaction mixture was then evaporated under reduced pressure andtriturated with MTBE to give2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acidas white solid (2 g, 78%). ¹H NMR (400 MHz, DMSO) δ ppm 13.27 (s, 1H),11.12 (s, 1H), 7.82-7.78 (m, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 5.13-5.04 (m, 1H), 4.99 (s, 2H), 2.94-2.85 (m, 1H), 2.73-2.57(m, 2H), 2.07-2.02 (m, 1H). LCMS (ESI⁺) m/z 333 (M+H)⁺.

Tert-Butyl (5-((5-aminopentyl)oxy)pentyl)carbamate (Intermediate E)

Step 1—Tert-Butyl (5-hydroxypentyl)carbamate

To a stirred solution of 5-aminopentan-1-ol (10.0 g, 96.9 mmol) in DCM(75 mL) was added Boc-anhydride (25.4 g, 116.3 mmol) dropwise at 0° C.The resulting reaction mixture was stirred at room temperature for 1 h.The reaction mixture was then transferred into ice water and theresulting mixture was extracted using DCM (3×100 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated under reduced pressure to give tert-butyl(5-hydroxypentyl)carbamate as colorless oil (16 g, 81%). ¹H NMR (400MHz, DMSO) δ 4.56 (bs, 1H), 3.69-3.64 (m, 2H), 3.17-3.12 (m, 2H),1.64-1.62 (m, 2H), 1.54-1.53 (m, 6H), 1.51-1.49 (m, 1H), 1.46 (s, 9H),1.43-1.37 (m, 2H).

Step 2—Tert-Butyl (5-((5-azidopentyl)oxy)pentyl)carbamate

To a stirred solution of tert-butyl (5-hydroxypentyl)carbamate (2.5 g,12.3 mmol) in DMF (20 mL) was added NaI (catalytic amount) and NaH (0.74g, 18.4 mmol, 60% dispersion in mineral oil) at room temperature. Theresulting reaction mixture was stirred at room temperature for 0.5 h. Tothis reaction mixture 1-azido-5-bromopentane (3.55 g, 18.4 mmol,Intermediate A) in DMF (5 mL) was added dropwise at room temperature.The resulting reaction mixture was stirred at room temperature for 16 h.The reaction mixture was then transferred into ice water and theresulting mixture was extracted using ethyl acetate (3×100 mL). Thecombined organic layers were dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure. The crudeproduct was purified using silica gel column chromatography (6%EAc-Hexanes) to give tert-butyl (5-((5-azidopentyl)oxy)pentyl)carbamateas colorless oil (0.85 g, 22%). LC-MS (ESI⁺) m/z 315.39 (M+H)⁺.

Step 3—Tert-Butyl (5-((5-aminopentyl)oxy)pentyl)carbamate

To a stirred solution of tert-butyl(5-((5-azidopentyl)oxy)pentyl)carbamate (0.2 g, 0.6 mmol) in methanol (5mL) was added 10% Pd/C (0.1 g, 50% wet) at room temperature undernitrogen atmosphere. The resulting reaction mixture was stirred underhydrogen gas (5 kg/cm² pressure) in auto clave at rt for 5 h. Thereaction mixture was filtered through a pad of celite under vacuum andwashed with MeOH (20 mL). The filtrate was evaporated under reducedpressure to give tert-butyl (5-((5-aminopentyl)oxy)pentyl)carbamate ascolorless oil (0.15 g, 82%). LC-MS (ESI⁺) m/z 289.43 (M+H)⁺.

Tert-Butyl (5-(2-((5-aminopentyl)oxy)ethoxy)pentyl)carbamate(Intermediate F)

Step 1—((2-((5-bromopentyl)oxy)ethoxy)methyl)benzene

A solution of 2-(benzyloxy) ethan-1-ol (1.67 g, 10.96 mmol),1,5-dibromopentane (10.0 g, 43.0 mmol), and ammonium bromide (0.5 g) in8N NaOH (20 mL) was stirred at room temperature for 25 h. The reactionmixture was then transferred into ice water mixture, the pH was adjustedto 6-7, and resulting mixture was extracted using n-hexane (3×100 mL).The combined organic layer was dried over anhydrous sodium sulphate andfiltered. The filtrate was evaporated under vacuum to give((2-((5-bromopentyl)oxy)ethoxy)methyl)benzene as colorless liquid (23 g,95%). LC-MS (ESI⁺) m/z 303 (M+H)⁺².

Step 2—((2-((5-azidopentyl)oxy)ethoxy)methyl)benzene

A solution of ((2-((5-bromopentyl)oxy)ethoxy) methyl)benzene (23.0 g,76.6 mmol) and sodium azide (7.47 g, 114.93 mmol) in DMF (125 mL) washeated to 60° C. and stirred for 18 h. The reaction mixture was thentransferred into ice water and the resulting mixture was extracted usingethyl acetate (3×200 mL). The combined organic layers were dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the crude product was purified using silica gelcolumn chromatography (10% EtOAc-Hexane) to give((2-((5-azidopentyl)oxy)ethoxy)methyl)benzene as a colorless liquid(10.5 g, 82%). LC-MS (ESI⁺) m/z 281.2 (M+18)⁺.

Step 3—Tert-Butyl (5-(2-hydroxyethoxy)pentyl)carbamate

A solution of ((2-((5-azidopentyl)oxy)ethoxy) methyl)benzene (10.5 g,39.9 mmol), 10% Pd/(OH)₂ (50% wet) (5 g) and Boc anhydride (13.04 g,59.84 mmol) in MeOH (100 mL) and acetic acid (1 mL) was stirred in anautoclave. The reaction mixture was heated to 60° C. under hydrogen gas(30 kg/cm² pressure) for 48 h. The reaction mixture was filtered througha pad of celite and washed with methanol (100 mL). The filtrate wasevaporated under reduced pressure and the crude product (with tert-butyl(5-(2-(benzyloxy)ethoxy)pentyl)carbamate as a side product) was purifiedusing silica gel column chromatography (20% EtOAc-hexane) to givetert-butyl (5-(2-hydroxyethoxy)pentyl)carbamate as colorless oil (1.6 g,13%).

Step 4—Tert-Butyl (5-(2-((5-azidopentyl)oxy)ethoxy)pentyl)carbamate

A solution of tert-butyl (5-(2-hydroxyethoxy)pentyl)carbamate (1.6 g,6.5 mmol), TBAB (0.3 g, catalytic amount) and 1-azido-5-bromopentane(1.85 g, 9.71 mmol, Intermediate A) were dissolved in a mixture oftoluene (30 mL) and 8 N NaOH (20 mL) and heated at 80° C. for 24 h. Thereaction mixture was then transferred into ice water and the resultingmixture was extracted using ethyl acetate (3×50 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated under reduced pressure and the crude productwas purified using silica gel column chromatography (25% EtOAc-Hexane)to give tert-butyl (5-(2-((5-azidopentyl)oxy)ethoxy)pentyl)carbamate asa colorless oil (0.7 g, 30%). LC-MS (ESI⁺) m/z 359.3 (M+H)⁺.

Step 5—Tert-Butyl (5-(2-((5-aminopentyl)oxy)ethoxy)pentyl)carbamate

A solution of tert-butyl (5-(2-((5-azidopentyl)oxy)ethoxy)pentyl)carbamate (0.7 g, 19.9 mmol) and 10 wt % Pd/C (50%wet) (0.05 g) was dissolved in MeOH (10 mL) in an autoclave. Thereaction mixture was heated to 50° C. under hydrogen gas (20 kg/cm²pressure) for 4 h. Upon completion, the reaction mixture was filteredthrough a pad of celite and washed with methanol (20 mL). The filtratewas evaporated under reduced pressure to give as tert-butyl(5-(2-((5-aminopentyl)oxy)ethoxy)pentyl)carbamate as a colorless oil(0.55 g) which was used directly in the next step without furtherpurification.

(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideHydrochloride (Intermediate G)

Step 1—4-(4-methylthiazol-5-yl)benzonitrile

To a solution of 4-bromobenzonitrile (1.0 g, 5.5 mmol) and palladiumacetate (0.061 g, 2.75 mmol) in dimethyl acetamide (5 mL) was addedpotassium acetate (1.08 g, 11.0 mmol) and 4-methylthiazole (1 mL, 11.0mmol) at rt. The reaction mixture was then heated and stirred at 130° C.for 18 h. The reaction mixture was transferred into ice water and theresulting mixture was extracted using DCM (3×20 mL). The combinedorganic layers were dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated under reduced pressure and the crude productwas purified using silica gel column chromatography (10% EtOAc-hexane)to give 4-(4-methylthiazol-5-yl)benzonitrile as yellow solid (0.6 g,55%). LC-MS (ESI⁺) m/z 200 (M+H)⁺.

Step 2—Tert-Butyl (4-(4-methylthiazol-5-yl)benzyl)carbamate

To a stirred solution of 4-(4-methylthiazol-5-yl)benzonitrile (0.6 g,3.0 mmol) in methanol (50 mL) was added NiCl₂·6H₂O (0.07 g, 0.3 mmol)and boc anhydride (1 mL, 4.5 mmol) at 0° C. and stirred for 15 minutes.After 15 minutes, NaBH₄ (0.8 g, 21.0 mmol) was added in portions over 30minutes at 0° C. and stirred additional for 30 minutes. Thentriethylamine (0.8 mL, 6.0 mmol) was added and the mixture was stirredfor a further 3 h. The reaction mixture was then evaporated under vacuumand diluted with ethyl acetate (50 mL) and filtered through celite. Thefiltrate was washed using water (50 mL). The combined organic layerswere dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure and the crude product was purifiedusing silica gel column chromatography (15% EtOAc-Hexane) to givetert-butyl (4-(4-methylthiazol-5-yl)benzyl)carbamate as yellow semisolid(0.5 g, 55%). LC-MS (ESI⁺) m/z 305.2 (M+H)⁺.

Step 3—(4-(4-methylthiazol-5-yl)phenyl)methanamine Hydrochloride

To a stirred solution of tert-butyl(4-(4-methylthiazol-5-yl)benzyl)carbamate (0.5 g, 1.6 mmol) in DCM (5mL) was added 4N HCl in dioxane (1 mL) and the reaction mixture wasstirred at rt for 3 h. The reaction mixture was then evaporated undervacuum and triturated using diethyl ether to give(4-(4-methylthiazol-5-yl)phenyl)methanamine hydrochloride as yellowsolid (0.35 g, 89%). LC-MS (ESI⁺) m/z 205.2 (M+H)⁺.

Step 4—Tert-Butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate

To a solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(0.25 g, 1.08 mmol, CAS #13726-69-7) in DCM (5 mL) was addedN-hydroxysuccinimide (0.16 g, 1.40 mmol) and EDC-HCl (0.25 g, 1.30 mmol)and the reaction was stirred at rt for 3 h. After 3 h,(4-(4-methylthiazol-5-yl)phenyl)methanamine hydrochloride (0.31 g, 1.30mmol) and DIPEA (0.6 mL, 3.24 mmol) was added and the reaction mixturewas stirred at room temperature for 18 h. The reaction mixture wasdiluted with saturated NaHCO₃ solution (50 mL) and extracted in DCM (50mL×3). The combined organic layers were dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the crude product was purified using silica gel columnchromatography (2% MeOH-DCM) to give tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylateas yellow solid (0.3 g, 66%). LC-MS (ESI⁺) m/z 418.8 (M+H)⁺.

Step5—(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideHydrochloride

To a stirred solution of tert-butyl(2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate(0.3 g, 0.7 mmol) in DCM (10 mL) was added 4N HCl in dioxane (1 mL) andthe reaction mixture was stirred at rt for 3 h. The reaction mixture wasthen evaporated under vacuum and triturated using diethyl ether to give(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride as yellow solid (0.2 g, 79%). LC-MS (ESI⁺) m/z 318.0(M+H)⁺.

Step 6—Tert-Butyl((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

To a solution of(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride (0.2 g, 0.6 mmol),(S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (0.13 g,0.57 mmol, CAS #62965-35-9) and DIPEA (0.4 mL, 2.28 mmol) in DMF (2 mL),was added HATU (0.3 g, 0.63 mmol) and the reaction mixture was stirredat rt for 1 h. The reaction mixture was then transferred into ice waterand the resulting mixture was extracted using ethyl acetate (3×20 mL).The combined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure and thecrude product was purified using silica gel column chromatography (4%MeOH-DCM) to give tert-butyl((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamateas yellow semisolid (0.15 g, 44%). LC-MS (ESI⁺) m/z 531.81 (M+H)⁺.

Step7—(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideHydrochloride

To a stirred solution of tert-butyl((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(0.15 g, 0.28 mmol) in DCM (10 mL) was added 4N HCl in dioxane (1 mL)and the reaction mixture was stirred at rt for 3 h. The reaction mixturewas then evaporated under vacuum and solid was triturated using diethylether to give(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride as yellow solid (0.12 g, 91%). ¹H NMR (400 MHz, DMSO) δ9.10 (s, 1H), 8.78 (t, J=6 Hz, 1H), 8.27-8.07 (m, 3H), 7.50-7.31 (m,4H), 4.55 (t, J=8.2 Hz, 1H), 4.50-4.30 (m, 2H), 4.29-4.15 (m, 1H),4.05-3.85 (m, 1H), 3.84-3.70 (m, 1H), 3.65-3.45 (m, 1H), 2.46 (s, 3H),2.20-2.05 (m, 1H), 1.95-1.80 (m, 1H), 1.32-1.27 (m, 1H), 1.03 (s, 9H).LC-MS (ESI⁺) m/z 431.85 (M+H)⁺.

Tert-Butyl((1R,3R)-3-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)Carbamate (Intermediate H)

Step 1—Methyl(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate

To a stirred solution of methyl (1R,3R)-3-aminocyclobutane-1-carboxylatehydrochloride (1.0 g, 6.1 mmol), TEA (2 mL, 12 mmol) in DCM (5 mL) wasadded and Boc anhydride (1.7 g, 7.8 mmol) at 0° C. The reaction mixturewas then stirred at rt for 3 h. The reaction mixture was thentransferred into ice water and the resulting mixture was extracted usingethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to give methyl(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate as awhite solid (1.2 g, 72%). ¹H NMR (400 MHz, DMSO) δ 7.26 (d, J=7.6 Hz,1H), 4.10 (m, 1H), 3.62 (s, 3H), 2.96-2.91 (m, 1H), 2.36-2.31 (m, 2H),2.19-2.12 (m, 2H), 1.42 (s, 9H).

Step 2—Tert-Butyl ((1R,R)-3-(hydroxymethyl)cyclobutyl)carbamate

To a stirred solution of methyl(1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate (1.0 g,4.4 mmol) in THF (20 mL) was added 3M lithium borohydride (9 mL, 9 mmol)at 0° C. Then the reaction mixture was heated and stirred at 60° C. for3 h. The reaction mixture was then transferred into dilute NaOH and theresulting mixture was extracted using ethyl acetate (3×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure and thecrude product was purified using silica gel column chromatography (3%MeOH-DCM) to give tert-butyl((1r3r)-3-(hydroxymethyl)cyclobutyl)carbamate as a white solid (0.8 g,91%). ¹H NMR (400 MHz, DMSO) δ 4.77 (bs, 1H), 4.24 (d, J=6.8 Hz, 1H),3.71 (d, J=6.0 Hz, 3H), 2.39 (s, 1H), 2.25-2.21 (m, 2H), 2.05-1.98 (m,2H), 1.67-1.29 (m, 13H).

Step 3—((1R, 3R)-3-((tert-butoxycarbonyl) amino)cyclobutyl)methylMethane Sulfonate

To a stirred solution of tert-butyl((1R,3R)-3-(hydroxymethyl)cyclobutyl)carbamate (0.8 g, 4.0 mmol) indichloromethane (20 mL) was added triethylamine (1.67 mL, 11.91 mmol) at0° C. Mesyl chloride (0.82 mL, 5.96 mmol) was then added and the mixturewas allowed to warm to rt and stirred for 2 h. The reaction mixture wasthen transferred into ice water and the resulting mixture was extractedusing ethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to give ((1R, 3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methyl methane sulfonate as yellow solid (0.9 g, 81%).

Step 4—Tert-Butyl((1R,3R)-3-(12-phenyl-2,5,8,11-tetraoxadodecyl)cyclobutyl)carbamate

A solution of 2-(2-(2-(benzyloxy)ethoxy) ethoxy)ethan-1-ol (0.43 g, 1.79mmol, Intermediate T),((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methylmethanesulfonate (2.9 g, 10.39 mmol) and TBAB (20 mg,) in toluene:8NNaOH (1:1, 16 mL) was stirred at 90° C. for 16 h. The reaction mixturewas then transferred into ice water and the resulting mixture wasextracted using ethyl acetate (3×25 mL). The combined organic layer wasdried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure and the crude product was purifiedusing silica gel column chromatography (45% EtOAc-Hexane) to givetert-butyl((1R,3R)-3-(18-phenyl-2,5,8,11,14,17-hexaoxaoctadecyl)cyclobutyl)carbamateas a light yellow liquid (0.7 g, 76%). LC-MS (ESI⁺) m/z 441.50 (M+H)⁺.

Step 5—Tert-Butyl((1R,3R)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate

To a stirred solution of tert-butyl((1r,3r)-3-(12-phenyl-2,5,8,11-tetraoxadodecyl) cyclobutyl)carbamate(0.7 g, 1.65 mmol) in EtOH (20 mL) was added 10% Pd/C (50% wet) (0.7 g)and the reaction mixture was stirred under hydrogen atmosphere at rt for6 h. The reaction mixture was then filtered through celite andevaporated under reduced pressure to give tert-butyl((1R,3R)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamateas a colorless liquid (0.5 g). LC-MS (ESI⁺) m/z 351.45 (M+H)⁺.

Step6—2-(2-(2-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methoxy)ethoxy)ethoxy)ethylMethanesulfonate

To a stirred solution of tert-butyl((1R,3R)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate(0.5 g, 1.5 mmol) and triethylamine (0.7 mL, 4.5 mmol) indichloromethane (5 mL) was added mesyl chloride (0.15 mL, 1.8 mmol) at0° C. The reaction was allowed to warm to rt and stirred for 3 h. Thereaction mixture was then transferred into ice water and the resultingmixture was extracted using DCM (3×25 mL). The combined organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure to give2-(2-(2-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methoxy)ethoxy)ethoxy)ethylmethanesulfonate as a light yellow solid (0.53 g, 85%).

Step 7—Tert-Butyl ((1R,3R)-3-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate

To a stirred solution of2-(2-(2-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methoxy)ethoxy)ethoxy)ethylmethanesulfonate (0.53 g, 1.30 mmol) in DMF (4 mL) was added sodiumazide (0.13 g, 1.93 mmol) at rt. Then the reaction mixture was heated at65° C. for 5 h. The reaction mixture was then transferred into ice waterand the resulting mixture was extracted using ethyl acetate (3×25 mL).The combined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to affordcrude product. The crude product was purified using silica gel columnchromatography (2% MeOH-DCM) to give tert-butyl((1R,3R)-3-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamateas a light yellow liquid (0.45 g, 82%). LC-MS (ESI⁺) m/z 376 (M+18)⁺.

Step 8—Tert-Butyl((1R,3R)-3-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate

To a stirred solution of tert-butyl((1R,3R)-3-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamate(0.45 g, 1.25 mmol) in EtOH (20 mL) was added 10% Pd/C (50% wet) (0.45g) and the reaction mixture was stirred under hydrogen atmosphere for 5h. The reaction mixture was filtered through celite and concentratedunder reduced pressure to givetert-butyl((1r,3r)-3-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclobutyl)carbamateas a colorless liquid (0.35 g). LC-MS (ESI⁺) m/z 334.45 (M+18)⁺.

12-((tert-butoxycarbonyl)amino)dodecanoic Acid (Intermediate I)

A mixture of 12-aminododecanoic acid (2.0 g, 9.3 mmol, CAS #693-57-2),Boc anhydride (2.4 mL, 10.2 mmol) and triethylamine (1.4 mL, 10.2 mmol)in methanol (50 mL) was refluxed for 18 h. The reaction mixture thencooled to rt and was concentrated under vacuum and diluted with ethylacetate (200 mL). The organic layer was washed with 5% citric acid (100mL×2), water (100 mL), dried over anhydrous sodium sulphate, andevaporated to give 12-((tert-butoxycarbonyl)amino)dodecanoic acid as awhite solid (2.5 g, 85%). LC-MS (ESI⁺) m/z 314.2 (M−H)⁺.

1-phenyl-2,5,8,11-tetraoxatridecan-13-ol (Intermediate J)

To a stirred solution of2,2′-((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethan-1-ol) (20.0 g, 103mmol) in THF (150 mL) was added 60% NaH in paraffin (2.06 g, 51.5 mmol)at 10° C. in an ice water bath and the reaction mixture was stirred 0.5h. To this reaction mixture benzyl bromide (5.9 mL, 51.49 mmol) in THF(50 mL) was added dropwise at 10° C. over 1.5 h. The resulting reactionmixture was allowed to warm to rt and stirred for 16 h. The reactionmixture was then transferred into ice water and the resulting mixturewas extracted using ethyl acetate (3×100 mL). The combined organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure and the crude product was purifiedusing silica gel column chromatography (3% MeOH-DCM) to give1-phenyl-2,5,8,11-tetraoxatridecan-13-ol as a yellow oil (15 g, 51%).LC-MS (ESI⁺) m/z 284.35 (M+H₂O)⁺.

Tert-Butyl((1R,4R)-4-(13-amino-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate(Intermediate K)

Step 1—Methyl(1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylate

To a stirred solution of methyl (1R,4R)-4-aminocyclohexane-1-carboxylatehydrochloride (6.5 g, 31.0 mmol) and triethylamine (6.8 mL, 92.94 mmol)in DCM (100 mL) was added Boc-anhydride (8.1 g, 37.18 mmol) dropwise at0° C. The resulting reaction mixture was warmed to rt and stirred for1.5 h. The reaction mixture was then transferred into ice water and theresulting mixture was extracted using DCM (3×100 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure to give methyl(1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylate as awhite solid (6.6 g, 83%). LC-MS (ESI⁺) m/z 258.2 (M+H)⁺.

Step 2—Tert-Butyl ((1R,4R)-4-(hydroxymethyl)cyclohexyl)carbamate

To a stirred solution of methyl(1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexane-1-carboxylate (5.5 g,21.4 mmol) in THF (20 mL) was added 3 M LiBH₄ in THF (16 mL, 43 mmol)dropwise at 0° C. The resulting reaction mixture then heated to 75° C.and stirred for 1 h. The reaction mixture was then transferred into 5%citric acid solution. The pH of the reaction mixture was adjusted to pH8 to 9 with 8 N NaOH solution. The resulting mixture was then extractedusing ethyl acetate (3×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure and the crude product was purified using silicagel column chromatography (25% EAc-Hexanes) to give tert-butyl((1r,4r)-4-(hydroxymethyl)cyclohexyl)carbamate as white solid (1.5 g,31%). LC-MS (ESI⁺) m/z 230.2 (M+H)⁺.

Step 3—((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate

To a solution of tert-butyl((1R,4R)-4-(hydroxymethyl)cyclohexyl)carbamate (1.8 g, 7.8 mmol) in DCM(50 mL) was added triethylamine (2.36 g, 23.4 mmol) and MsCl (0.9 mL,11.7 mmol) at 0° C. and the reaction was stirred for 90 minutes. Thereaction mixture was then diluted with water (50 mL) and product wasextracted in DCM (50 mL×3). The organic layer was dried over anhydroussodium sulphate, filtered and evaporated in vacuum to give((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate as a light brown solid (1.8 g, 75%); LC-MS (ESI⁺) m/z308.2 (M+H)⁺.

Step 4—tert-butyl((1R,4R)-4-(15-phenyl-2,5,8,11,14-pentaoxapentadecyl)cyclohexyl)carbamate

To a solution of 1-phenyl-2,5,8,11-tetraoxatridecan-13-ol (1.4 g, 4.9mmol, Intermediate J) in toluene (20 mL) and 8N NaOH (20 mL) was added acatalytic amount of TBAB and the reaction was stirred for 15 minutes atrt. After 15 minutes,((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate (1.8 g, 5.9 mmol) was added and the reaction mixturewas refluxed for 16 h. The reaction mixture was then diluted with water(200 mL) and extracted in ethyl acetate (250 mL×3). The organic layerwas dried over anhydrous sodium sulphate, filtered and evaporated invacuo. The crude product was purified by silica gel columnchromatography (45-50% EtOAC-Hexane) to give tert-butyl((1R,4R)-4-(15-phenyl-2,5,8,11,14-pentaoxapentadecyl)cyclohexyl)carbamateas a yellow semisolid (0.8 g, 33%); LC-MS (ESI⁺) m/z 496.5 (M+H)⁺.

Step 5—Tert-Butyl((1R,4R)-4-(13-hydroxy-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1R,4R)-4-(15-phenyl-2,5,8,11,14-pentaoxapentadecyl)cyclohexyl)carbamate(0.8 g, 1.6 mmol) in ethanol (50 mL) was added 10% Pd/C (50% wet) (0.8g) and acetic acid (0.2 mL) at room temperature with hydrogen gasbubbling through the solution for 2 h. The reaction mixture was thenfiltered through a pad of celite and the filtrate was evaporated to givetert-butyl((1R,4R)-4-(13-hydroxy-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate asa brown oil (0.7 g, 64%); LC-MS (ESI⁺) m/z 406.4 (M+H)⁺.

Step 61-((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,11-tetraoxatridecan-13-ylmethanesulfonate

To a stirred solution of tert-butyl((1R,4R)-4-(13-hydroxy-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate(0.37 g, 0.91 mmol) in DCM (10 mL) was added triethylamine (0.3 mL, 2.7mmol) at 0° C. followed by mesyl chloride (0.11 g, 1.37 mmol) then thereaction was stirred for 2 h. The reaction was then quenched with water(50 mL) and product was extracted using DCM (50 mL×3). The organic layerwas dried over anhydrous sodium sulphate and evaporated in vacuo to give1-((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,11-tetraoxatridecan-13-ylmethanesulfonate as a yellow oil (0.37 g; 82%).

Step 7—tert-butyl((1r,4r)-4-(13-azido-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate

To a stirred solution of1-((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,11-tetraoxatridecan-13-ylmethanesulfonate (0.36 g, 0.74 mmol) in DMF (5 mL) was added NaN₃ (0.072g, 1.11 mmol) and the reaction mixture was heated at 70° C. for 2 h. Thereaction mixture was then cooled to rt and diluted with water (250 mL)and extracted in ethyl acetate (100 mL×3). The organic layer was driedover anhydrous sodium sulphate and evaporated in vacuo to give and thecrude product was purified by silica gel column chromatography (40%EtOAc-Hexane) to give tert-butyl((1r,4r)-4-(13-azido-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate as ayellow semisolid (0.29 g; 90%); LC-MS (ESI⁺) m/z 448.8 (M+18)⁺.

Step 8—Tert-Butyl((1r,4r)-4-(13-amino-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1R,4R)-4-(13-azido-2,5,8,11-tetraoxatridecyl)-cyclohexyl)carbamate(0.29 g, 0.67 mmols) in ethanol (20 mL) was added 10% Pd(OH)₂/C (50%wet) (0.29 g) at rt and the reaction mixture was stirred in autoclaveunder hydrogen gas (20 kg/cm² pressure) for 5 h. The reaction mixturewas filtered through a pad of celite and the filtrate was evaporated invacuo to give tert-butyl((1R,4R)-4-(13-amino-2,5,8,11-tetraoxatridecyl)cyclohexyl)carbamate as ayellow semisolid (0.17, 62%); LC-MS (ESI⁺) m/z 405.4 (M+H)⁺.

6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinicAcid (Intermediate L)

Step 1—Methyl 6-chloro-4-(cyclopropylamino)nicotinate

A solution of methyl 4,6-dichloronicotinate (10.0 g, 48.5 mmol), DIPEA(6.26 g, 48.5 mmol, 8.23 mL) and cyclopropylamine (3.04 g, 53.4 mmol) inDMA (80 mL) was stirred at 90° C. for 3 h. The reaction mixture was thentransferred into ice water and the resulting mixture was extracted usingethyl acetate (3×25 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the crude product was purified using silica gelcolumn chromatography (10% EtOAc-Hexane) to give methyl6-chloro-4-(cyclopropylamino)nicotinate as a white solid (8.5 g, 77%).¹H NMR (400 MHz, DMSO-d6) δ 8.538 (s, 1H), 8.079 (s, 1H), 7.040 (s, 1H),3.826 (s, 3H), 2.634-2.594 (m, 1H), 0.892-0.846 (m, 2H), 0.595-0.557 (m,2H).

Step 2—6-chloro-4-(cyclopropylamino)nicotinic Acid

A stirred solution of methyl 6-chloro-4-(cyclopropylamino)nicotinate(6.8 g, 30.0 mmol) in ethanol (70 mL) was cooled to 0-10° C. Then asolution of lithium hydroxide (3.6 g, 85.7 mmol in water (10 mL) wasadded. The reaction mixture was allowed to warm to rt and was stirredfor 3 h. The reaction mixture was then transferred into ice water andthe resulting mixture was extracted using ethyl acetate (2×100 mL). Theaqueous layer was acidified by addition of saturated citric acidsolution until the pH=3-4. The mixture was then extracted with ethylacetate (3×250 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure and the crude product was triturated using hexane to give6-chloro-4-(cyclopropylamino)nicotinic acid as an off-white solid (5 g,78%). ¹H NMR (400 MHz, DMSO-d6) δ 13.415 (bs, 1H), 8.525 (s, 1H) 8.318(s, 1H), 7.007 (s, 1H), 2.616-2.592 (m, 1H), 0.891-0.845 (m, 2H),0.620-0.564 (m, 2H).

Step 3—Tert-Butyl 6-chloro-4-(cyclopropylamino)nicotinate

A stirred solution 6-chloro-4-(cyclopropylamino)nicotinic acid (2.5 g,11.74 mmol) and DMF-DTA (10.2 g, 50.3 mmol) in toluene (50 mL) washeated at 110° C. for 16 h. The reaction mixture was then transferredinto ice water and the resulting mixture was extracted using ethylacetate (3×250 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure and the crude product was purified using silica gel columnchromatography (6% EtOAc-Hexane) to give tert-butyl6-chloro-4-(cyclopropylamino)nicotinate as a white solid (2.23 g, 70%).LC-MS (ESI⁺) m/z 269.3 (M+H)⁺.

Step 4—Tert-Butyl6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)Nicotinate

Under an atmosphere of argon, 1H-pyrazolo[3,4-b]pyridine-5-carbonitrile(1.0 g, 6.94 mmol), tert-butyl 6-chloro-4-(cyclopropylamino)nicotinate(2.05 g, 7.63 mmol), potassium carbonate (2.9 g, 20.83 mmol), Xantphos(1.61 g, 2.77 mmol) and Pd(dba)₂ (1.6 g, 2.77 mmol) in 1,4-dioxane (50mL) was heated at 120° C. for 20 h. The reaction mixture was filteredthrough celite and washed with ethyl acetate (3×300 mL). The combinedorganic layer was washed with water (400 mL), dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure and the crude product was purified using silica gel columnchromatography (1% MeOH-DCM) to give tert-butyl6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinate as a brown solid (0.6 g, 21%). LC-MS (ESI⁺) m/z 377.3 (M+H)⁺

Step5—6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinicAcid (as the TFA Salt)

A solution of tert-butyl6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinate(0.4 g, 1.06 mmol) and TFA (4 mL) in DCM (10 mL) was stirred at rt for 6h. The organic solvent was evaporated and the residue was trituratedwith MTBE (20 mL) to give6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinicacid as the TFA salt as a white solid (0.3 g, 88%). ¹H NMR (400 MHz,DMSO-d6) δ 13.38 (bs, 1H), 9.10 (d, J=2 Hz, 1H), 9.04 (d, J=2 Hz, 1H),8.76 (s, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 2.66-2.60 (m,1H), 0.93-0.89 (m, 2H), 0.65-0.62 (m, 2H).

1,6-naphthyridin-2-amine (Intermediate M)

Step 1—Tert-Butyl (1,6-naphthyridin-2-yl)carbamate

To a stirred solution of 1,6-naphthyridine-2-carboxylic acid (20.0 g,114 mmol) in t-BuOH (200 mL) was added Et₃N (16 mL, 114 mmol) anddiphenyl phosphoryl azide (37.0 g, 137 mmol) respectively at rt. Theresulting mixture then heated to 80° C. and stirred for 24 h. Thereaction mixture was evaporated carefully under vacuum, diluted with icewater and resulting solid was collected by filtration. The solid wastreated with hot ethanol and again filtered and dried under vacuum togive tert-butyl (1,6-naphthyridin-2-yl)carbamate as a light brown solid(13.1 g, 46%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H), 9.20 (s, 1H),8.61 (d, J=6 Hz, 1H), 8.47 (d, J=9.2 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H),7.62 (s, 1H), 1.50 (s, 9H). LC-MS (ESI⁺) m/z 246.2 (M+H)⁺

Step 2—1,6-naphthyridin-2-amine

To a stirred solution of tert-butyl (1,6-naphthyridin-2-yl)carbamate(4.37 g, 17.8 mmol) in MeOH:DCM (40 mL, 3:1 ratio) was added 4N HCl indioxane (15 mL) at 0° C. The resulting reaction mixture was allowed towarm to rt and stirred for 18 h. The reaction mixture was thenevaporated under vacuum and diluted with 30 mL of water. SaturatedNaHCO₃ solution (15 mL) was added and the resulting mixture wasextracted using EtOAc (2×50 mL). The combined organic layers were driedunder vacuum to give 1,6-naphthyridin-2-amine as a white solid (2.45 g,94%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.43 (d, J=6 Hz, 1H),8.14 (d, J=8.8 Hz, 1H), 7.72 (bs, 2H), 7.45 (d, J=6 Hz, 1H), 6.96 (d,J=8.8 Hz, 1H); LCMS (ESI⁺) m/z 146.4 (M+H)⁺.

(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinic Acid(Intermediate N)

Step 1—Methyl 6-chloro-4-(cyclopropylamino)nicotinate

To a stirred solution of methyl 4,6-dichloronicotinate (10.0 g, 48.5mmol) in DMA (80 mL) was added DIPEA (6.6 mL, 48.5 mmol) andcyclopropylamine (3.7 mL, 53.0 mmol) at rt. The resulting mixture thenheated at 90° C. for 3 h. After 3 h, the reaction mixture was cooled tort and diluted with ice water. The resulting mixture was stirred for 20min and the solid precipitate was collected by filtration and driedunder vacuum. The crude product was purified by silica gel columnchromatography (10% EtOAc-hexanes) to give methyl6-chloro-4-(cyclopropylamino)nicotinate as a white solid (9.5 g, 87%).¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 8.20 (bs, 1H), 6.98 (s, 1H),3.89 (s, 3H), 2.51 (m, 1H), 0.91 (q, J=6.8 Hz, 2H), 0.61-0.65 (m, 2H);LC-MS (ESI⁺) m/z 227.2 (M+H⁺.

Step 2—Methyl6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinate

To a stirred solution of methyl 6-chloro-4-(cyclopropylamino)nicotinate(2.5 g, 11.8 mmol) and 1,6-naphthyridin-2-amine (1.6 g, 11.76 mmol,Intermediate M) in DMA (50 mL) was added Xantphos (2.5 g, 4.4 mmol) andCs₂CO₃ (5.76 g, 17.60 mmol) and resulting reaction mixture was degassedusing argon for 30 min. Then of Pd₂(dba)₃ (2.0 g, 2.2 mmol) was added.The resulting mixture was heated at 120° C. for 18 h. The reactionmixture was cooled to rt and ice water was added. The resulting solidprecipitate was collected by filtration and dried under vacuum. Thecrude product was purified by silica gel column chromatography (5%MeOH-DCM) to give methyl6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinate as ayellow solid (2.2 g, 59%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.5 (s, 1H),9.08 (s, 1H), 8.66 (s, 1H), 8.58-8.60 (m, 2H), 8.31 (d, J=8.8 Hz, 1H),8.03 (s, 1H), 7.61 (d, J=6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H), 3.80 (s,3H), 2.67-2.70 (m, 1H), 0.99-1.02 (m, 2H), 0.65-0.67 (m, 2H). LC-MS(ESI⁺) m/z 336.6 (M+H)⁺.

Step 3—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinicAcid

To a stirred solution of methyl6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinate (1.6 g,1.8 mmol) in methanol:water (30 mL, 1:1 ratio) was added NaOH (0.36 g, 5mmol) at rt. The resulting reaction mixture was then heated at 70° C.for 16 h. Upon completion, the reaction mixture was in vacuo and theresulting solid was triturated using ethyl acetate and collected byfiltration. The solid was taken in water and the pH was adjusted to 6-7using dilute HCl and the resulting solid was collected by filtration anddried under vacuum to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinic acid as adark yellow solid (0.45 g, 78%). LC-MS (ESI⁺) m/z 322.6 (M+H)⁺

(1R,3R)-3-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclobutane-1-carboxylicAcid (Intermediate O)

Step 1—Methyl(1R,3R)-3-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclobutane-1-carboxylate

To a stirred solution of methyl(1R,3R)-3-aminocyclobutane-1-carboxylate-HCl (0.2 g, 1.6 mmol) and6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinic acid (0.5g, 1.6 mmol, Intermediate N) in DMF (4 mL) was added DIPEA (0.9 mL, 4.7mmol) and PyBOP (1.2 g, 2.3 mmol) at rt. The resulting reaction mixturewas stirred at rt for 2 h. The reaction mixture was then transferredinto ice water and the resulting mixture was filtered, dried and driedunder reduced pressure. The crude product was triturated with MTBE anddried in vacuo to give methyl(1r,3r)-3-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclobutane-1-carboxylate as a yellow solid. (0.55 g, 81%). LC-MS (ESI⁺) m/z433.2 (M+H)⁺.

Step2—(1R,3R)-3-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclobutane-1-carboxylic Acid

To a stirred solution of methyl(1R,3R)-3-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclobutane-1-carboxylate(0.55 g, 1.27 mmol) in THF:MeOH (15 mL, 1:1) was dropwise added NaOH(0.16 g, 3.82 mmol) in 5 mL water at rt. The resulting reaction mixturewas stirred at rt for 3 h. The reaction mixture was then evaporatedunder vacuum, and water (10 mL) was added and the pH was adjusted to 6-7using 10% citric acid solution. The resulting mixture was then stirredfor 15 min, and the solid precipitate was filtered off and dried undervacuo to give(1R,3R)-3-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-nicotinamido)cyclobutane-1-carboxylicacid as a yellow solid. (0.4 g, 75%). ¹H NMR (400 MHz, DMSO) δ 11.18 (s,1H), 10.36 (s, 1H), 9.05 (d, J=7.2 Hz, 1H), 8.59-8.45 (m, 4H), 8.28-8.23(m, 1H), 7.58-7.03 (m, 4H), 4.52-4.46 (m, 1H), 2.91 (t, J=8.8 Hz, 1H),2.58-2.27 (m, 4H), 0.90 (m, 2H), 0.52 (m, 2H).

Ethyl 2-(4-aminopiperidin-1-yl)acetate Hydrochloride (Intermediate P)

Step 1—Methyl 2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)acetate

A solution of tert-butyl piperidin-4-ylcarbamate (0.5 g, 2.5 mmol),ethyl bromo acetate (0.45 g, 2.75 mmol) and DIPEA (0.65 mL, 3.76 mmol)in DCM (5 mL) was stirred at rt for 3 h. The reaction mixture was thentransferred into ice water and the resulting mixture was extracted usingDCM (3×20 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure to give methyl2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)acetate as a colorlessoil (0.55 g, 81%). LC-MS (ESI⁺) m/z 287.2 (M+H)⁺.

Step 2—Ethyl 2-(4-aminopiperidin-1-yl)acetate Hydrochloride

To a solution of ethyl2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)acetate (0.55 g, 1.92mmol) in DCM (10 mL) was added 4N HCl in dioxane (3 mL) at 0° C. andthen the reaction was allowed to warm to rt and stirred for 4 h. Thereaction mixture was then evaporated under vacuum and the solid wastriturated using MTBE (5 mL) to give ethyl2-(4-aminopiperidin-1-yl)acetate hydrochloride as white solid (0.3 g,86%). LC-MS (ESI⁺) m/z 187.2 (M+H)⁺.

Methyl 2-(3-aminoazetidin-1-yl)acetate 2,2,2-trifluoroacetate(Intermediate Q)

Step 1—Methyl 2-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)acetate

To a mixture of tert-butyl azetidin-3-ylcarbamate (0.5 g, 0.58 mmol) andK₂CO₃ (0.6 g, 0.87 mmol) in ACN (5 mL) at 0° C. was added a solution ofmethyl 2-bromoacetate (0.444 g, 0.58 mmol) in ACN (5 mL) at sametemperature and the reaction mixture was stirred for 25 minutes. Thereaction mixture was then diluted with water (100 mL) and product wasextracted in ethyl acetate (50 mL×3). The organic layer was dried overanhydrous sodium sulphate, filtered and evaporated in vacuo. The crudeproduct was purified by silica gel column chromatography (3% MeOH-DCM)to give methyl 2-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)acetate asa yellow semi-solid (0.15 g, 21%); LC-MS (ESI⁺) m/z 245.2 (M+H)⁺.

Step 2—Methyl 2-(3-aminoazetidin-1-yl)acetate 2,2,2-trifluoroacetate

To a stirred solution of methyl2-(3-((tert-butoxycarbonyl)amino)azetidin-1-yl)acetate (0.15 g, 0.61mmol) in DCM (10 mL) was added TFA (3 mL) at 0° C. and the reaction wasstirred for 3 h. The reaction mixture was then evaporated in vacuo andtriturated with diethyl ether to give methyl2-(3-aminoazetidin-1-yl)acetate 2,2,2-trifluoroacetate as a brownsemisolid (0.1 g, 63%); LC-MS (ESI⁺) m/z 145.16 (M+H)⁺.

2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (IntermediateR)

Step 1—5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic Acid

To a stirred solution of 4-fluoroisobenzofuran-1,3-dione (25 g, 150mmol, CAS #652-39-1) in DMF (100 mL) was added L-glutamine (22 g, 150mmol) at rt. The resulting reaction mixture was heated to at 90° C. andstirred for 2 h. The reaction mixture was then evaporated under reducedpressure, transferred into 4 N aqueous HCl solution and the resultingmixture was stirred for 36 h at rt. The solid precipitate was thenfiltered off, washed with cold water and dried under reduced pressure togive 5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acidas a white solid (28 g, 63%). LC-MS (ESI⁺) m/z 295 (M+H)⁺.

Step 2—2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione

To a stirred solution of5-amino-2-(4-fluoro-1,3-dioxoisoindolin-2-yl)-5-oxopentanoic acid (28 g,95 mmol) in acetonitrile (200 mL) was added CDI (19 g, 110 mmol) andDMAP (0.14 g, 1.1 mmol) at rt. The resulting reaction mixture thenheated to 90° C. and stirred for 5 h. The reaction mixture was thenevaporated under reduced pressure. The crude product was purified usingsilica gel column chromatography (2% MeOH-DCM) to give2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione as a yellowsolid (12 g, 46%). ¹H NMR (400 MHz, DMSO) δ ppm 11.16 (s, 1H), 7.98-7.93(m, 1H), 7.80-7.76 (m, 2H), 5.19-5.14 (m, 1H), 2.94-2.85 (m, 1H),2.63-2.54 (m, 2H), 2.09-2.04 (m, 1H).

Tert-Butyl (3-(3-aminopropoxy)propyl)carbamate (Intermediate S)

A solution of 3,3′-oxybis(propan-1-amine) (1.0 g, 7.6 mmol, CAS#2157-24-6), and Boc anhydride (0.83 g, 3.78 mmol) in DCM (8 mL) wasstirred at rt for 16 h. The reaction mixture was then transferred intoice water and the resulting mixture was extracted using DCM (3×50 mL).The combined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure. The crudeproduct was purified using silica gel column chromatography (5%MeOH-DCM) to give tert-butyl (3-(3-aminopropoxy)propyl)carbamate as awhite solid (0.36 g, 21%). ¹H NMR (400 MHz, DMSO) δ 10.34 (s, 1H), 9.05(s, 1H), (d, J=5.2 Hz, 3H), 8.42 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.14(d, J=7.6 Hz, 1H), 7.70-7.67 (m, 1H), 6.76 (bs, 1H), 3.70 (t, J=2.8 Hz,1H), 3.00-3.05 (m, 2H), 2.89-2.86 (m, 2H), 2.06 (s, 1H), 1.88 (d, J=12.4Hz, 2H), 1.77 (d, J=11.6 Hz, 2H), 1.48-1.21 (m, 17H). LC-MS (ESI⁺) m/z233.35 (M+H)⁺

2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-1-ol (Intermediate T)

To a stirred solution of 2,2′-(ethane-1,2-diylbis(oxy))bis(ethan-1-ol)(30 g, 200 mmol) in THF (125 mL) was added 60% NaH in paraffin (4 g, 100mmol) at 10° C. The resulting reaction mixture stirred at the sametemperature for 0.5 h. To this reaction mixture was then added benzylbromide (17 g, 100 mmol) in THF (125) dropwise at 10° C. over 1.5 h. Theresulting reaction mixture then stirred at rt for 16 h. The reactionmixture was then transferred into ice water and the resulting mixturewas extracted using DCM (3×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure and the crude product was purified using silicagel column chromatography (4% MeOH-DCM) to give2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-1-ol as a yellow oil (20 g, 42%).LC-MS (ESI⁺) m/z 241.35 (M+H)⁺

Tert-Butyl((1R,3R)-3-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate(Intermediate U)

Step 1—Methyl(1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate

To a stirred solution of methyl(1S,3S)-3-aminocyclopentane-1-carboxylate hydrochloride (4.5 g, 25 mmol)and TEA (10.5 mL, 75 mmol) in DCM (100 mL) was dropwise addedBoc-anhydride (6.6 g, 30 mmol) at 0° C. The resulting reaction mixturewas then allowed to warm to rt and then stirred for 1.5 h. The reactionmixture was then transferred into ice water and the resulting mixturewas extracted using DCM (3×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure and the crude product was purified using silicagel column chromatography (40% EAc-Hexanes) to give methyl(1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate as awhite solid (5.1 g, 84%). LC-MS (ESI⁺) m/z 261.3 (M+18)⁺.

Step 2—Tert-Butyl ((1S,3S)-3-(hydroxymethyl)cyclopentyl)carbamate

To a stirred solution of methyl(1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentane-1-carboxylate (2.5 g,10.2 mmol) in THF (50 mL) was added 4 M LiBH₄ in THF (5.13 mL, 20.4mmol) dropwise at 0° C. The resulting reaction mixture then heated to75° C. and stirred for 1 h. The reaction mixture was then transferredinto 5% citric acid solution. The pH of the solution was then adjustedto pH=8 to 9 with 8 N NaOH solution. The resulting mixture was extractedusing ethyl acetate (3×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure and crude product was purified using silica gelcolumn chromatography (3% MeOH-DCM) to give tert-butyl((1S,3S)-3-(hydroxymethyl)cyclopentyl)carbamate as a white solid (1.9 g,86%). LC-MS (ESI⁺) m/z 233.15 (M+18)⁺.

Step 3—((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methylmethanesulfonate

To a stirred solution of tert-butyl((1S,3S)-3-(hydroxymethyl)cyclopentyl)carbamate (1.6 g, 7.4 mmol) andTEA (3.1 mL, 22.3 mmol) in DCM (25 mL) was added Mesyl chloride (0.91mL, 11.14 mmol) dropwise at 0° C. The resulting reaction mixture wasallowed warm to room temperature and then stirred for 1 h. The reactionmixture was then transferred into water and the resulting mixture wasextracted using DCM (3×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure to give((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methylmethanesulfonate as a white solid (1.9 g, 87%). LC-MS (ESI⁺) m/z 238.3(M−56)⁺.

Step 4—Tert-Butyl((1R,3R)-3-(12-phenyl-2,5,8,11-tetraoxadodecyl)cyclopentyl)carbamate

To a stirred solution of 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-1-ol(1.3 g, 5.4 mmol, Intermediate T) and((1S,3S)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methylmethanesulfonate (1.9 g, 6.5 mmol) in toluene (20 mL) and 8 N AqueousNaOH solution (20 mL) was added TBAB (catalytic amount) at rt. Theresulting reaction mixture was then heated to 90° C. and stirred for 16h. The reaction mixture was then transferred into ice water and theresulting mixture was extracted using ethyl acetate (3×100 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure and thecrude product was purified using silica gel column chromatography (2%MeOH-DCM) to give tert-butyl((1R,3R)-3-(12-phenyl-2,5,8,11-tetraoxadodecyl)cyclopentyl)carbamate asa yellow oil (0.8 g, 41%). LC-MS (ESI⁺) m/z 338.4 (M−100)⁺.

Step 5—Tert-Butyl((1R,3R)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate

To a stirred solution of tert-butyl((1R,3R)-3-(12-phenyl-2,5,8,11-tetraoxadodecyl)cyclopentyl)carbamate(0.8 g, 1.8 mmol) in ethanol (25 mL) and acetic acid (0.3 mL) was added10% Pd/C (0.8 g, 50% wet) at rt under nitrogen atmosphere. The resultingreaction mixture was stirred under hydrogen gas (2 kg/cm² pressure) inan autoclave at rt for 1.5 h. The reaction mixture was then filteredthrough a pad of celite under vacuum and washed with MeOH (50 mL). Thefiltrate was evaporated under reduced pressure to give tert-butyl((1R,3R)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamateas a yellow oil (0.6 g, 94%). LC-MS (ESI⁺) m/z 248.5 (M−100)⁺.

Step6—2-(2-(2-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methoxy)ethoxy)ethoxy)ethyl Methanesulfonate

To a stirred solution of tert-butyl((1R,3R)-3-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate(0.6 g, 1.7 mmol) and TEA (0.75 mL, 5.18 mmol) in DCM (10 mL) was addedMesyl chloride (0.21 mL, 2.59 mmol) dropwise at 0° C. The resultingreaction mixture then warmed to rt and stirred for 1 h. The reactionmixture was then transferred into water and the resulting mixture wasextracted using DCM (3×100 mL). The combined organic layer was driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure to give2-(2-(2-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methoxy)ethoxy)ethoxy)ethylmethanesulfonate as a brown oil (0.72 g, 98%). LC-MS (ESI⁺) m/z 370.3(M−56)⁺.

Step 7—Tert-Butyl((1R,3R)-3-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)Carbamate

To a stirred solution of2-(2-(2-(((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclopentyl)methoxy)ethoxy)ethoxy)ethylmethanesulfonate (0.78 g, 1.83 mmol) in DMF (10 mL) was added NaN₃ (0.18g, 2.74 mmol) at rt. The resulting reaction mixture was then heated to65° C. and stirred for 2 h. The reaction mixture was then transferredinto water and the resulting mixture was extracted using ethyl acetate(3×100 mL). The combined organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the crude product was purified using silica gel columnchromatography (3% MeOH-DCM) to give tert-butyl((1R,3R)-3-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamateas a colorless oil (0.65 g, 95%). LC-MS (ESI⁺) m/z 390.4 (M+18)⁺.

Step 8—Tert-Butyl((1R,3R)-3-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate

To a stirred solution of tert-butyl((1R,3R)-3-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamate(0.75 g, 2.01 mmol) in ethanol (20 mL) was added 10% Pd/C (0.75 g, 50%wet) at rt under nitrogen atmosphere. The resulting reaction mixturethen stirred under hydrogen gas (15 kg/cm² pressure) in autoclave at rtfor 6 h. The reaction mixture was then filtered through a pad of celiteunder vacuum and washed with MeOH (50 mL). The filtrate was evaporatedunder reduced pressure to give tert-butyl((1R,3R)-3-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclopentyl)carbamateas a yellow oil (0.48 g, 69%). LC-MS (ESI⁺) m/z 347.5 (M+H)⁺.

Tert-Butyl (14-amino-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate(Intermediate V)

Step 1—14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate

To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (10 g, 41.96mmol, CAS #4792-15-8), silver oxide (14.6 g, 62.94 mmol) and NaI (7 g,46.56 mmol) in DCM (250 mL) was added tosyl chloride (8.5 g, 41.96 mmol)at 0° C. The reaction mixture was then allowed to warm to rt and stirredfor 1 h. The reaction mixture was then filtered through celite and thefiltrate was washed with 10% NaHCO₃ solution (125 mL). The organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasthen evaporated under reduced pressure and the crude product waspurified using silica gel column chromatography (3% MeOH-DCM) to give14-hydroxy-3,6,9,12-tetraoxatetradecyl 4-methylbenzenesulfonate as ayellow oil (13 g, 79%). LC-MS (ESI⁺) m/z 394.3 (M+H)⁺.

Step 2—5,8,11,14-tetraoxa-2-azahexadecan-16-ol

To a stirred solution of 14-hydroxy-3,6,9,12-tetraoxatetradecyl4-methylbenzenesulfonate (3.0 g, 7.7 mmol) in THF (10 mL) was added 2Mmethyl amine solution in THF (16 mL, 30.6 mmol) dropwise at rt. Theresulting reaction mixture then heated to 65° C. and stirred for 16 h.The reaction mixture was filtered and the filter cake was washed withTHF (20 mL). The filtrate was then evaporated under reduced pressure togive 5,8,11,14-tetraoxa-2-azahexadecan-16-ol as a yellow oil (1.8 g,94%). MASS (ESI⁺) m/z 252 (M+H)⁺.

Step 3—Tert-Butyl(14-hydroxy-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate

To a stirred solution of 5,8,11,14-tetraoxa-2-azahexadecan-16-ol (1.8 g,7.2 mmol) in DCM (50 mL) was added Boc-anhydride (9.36 g, 42.96 mmol)dropwise at 0° C. The resulting reaction mixture then warmed to rt andstirred for 2 h. The reaction mixture was then transferred into icewater and the resulting mixture was extracted using DCM (3×50 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure and thecrude product was purified using silica gel column chromatography (2%MeOH-DCM) to give tert-butyl(14-hydroxy-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate as a lightyellow oil (1.5 g, 59%). LC-MS (ESI⁺) m/z 351.44 (M+H)⁺.

Step 4—2,2,5-trimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-ylMethanesulfonate

To a stirred solution of tert-butyl(14-hydroxy-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate (1.5 g, 4.3mmol) and TEA (1.8 mL, 12.8 mmol) in DCM (30 mL) was added mesylchloride (0.5 mL, 6.4 mmol) dropwise at 0° C. The resulting reactionmixture then warmed to rt and stirred for 1 h. The reaction mixture wasthen transferred into water and the resulting mixture was extractedusing DCM (3×50 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure to give2,2,5-trimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-ylmethanesulfonate as a yellow oil (1.5 g, 82%).

Step 5—Tert-Butyl(14-azido-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate

To a stirred solution of2,2,5-trimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-ylmethanesulfonate (1.5 g, 3.5 mmol) in DMF (15 mL) was added sodium azide(0.34 g, 5.23 mmol) at rt. The resulting reaction mixture was thenheated to 65° C. and stirred for 2 h. The reaction mixture was thentransferred into ice water and the resulting mixture was extracted usingethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the crude product was purified using silica gelcolumn chromatography (40% EAc-Hexanes) to give tert-butyl(14-azido-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate as a lightyellow oil (1.2 g, 92%). LC-MS (ESI⁺) m/z 377.2 (M+H)⁺.

Step 6—Tert-Butyl(14-amino-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate

To a stirred solution of tert-butyl(14-azido-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate (1.2 g, 3.2mmol) in MeOH (30 mL) was added 10% Pd/C (1.2 g, 50% wet) at rt undernitrogen atmosphere. The resulting reaction mixture was then stirredunder hydrogen gas (15 kg/cm² pressure) in autoclave at rt for 2 h. Thereaction mixture was then filtered through a pad of celite under vacuumand washed with MeOH (30 mL). The filtrate was then evaporated underreduced pressure to give tert-butyl(14-amino-3,6,9,12-tetraoxatetradecyl)(methyl)carbamate as a colorlessoil (1 g, 91%). LC-MS (ESI⁺) m/z 351.7 (M+H)⁺.

Tert-Butyl((1R,4R)-4-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate(Intermediate W)

Step 1—Tert-Butyl((1R,4R)-4-(12-phenyl-2,5,8,11-tetraoxadodecyl)cyclohexyl)carbamate

To a stirred solution of((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methylmethanesulfonate (1.1 g, 4.6 mmol, synthesized via Steps 1-3 ofIntermediate K) and 2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethan-1-ol (1.7 g,5.5 mmol, Intermediate T) in toluene (20 mL) and 8 N Aqueous NaOHsolution (20 mL) was added TBAB (catalytic amount) at rt. The resultingreaction mixture was then heated to 90° C. and stirred for 16 h. Thereaction mixture was then transferred into ice water and the resultingmixture was extracted using ethyl acetate (3×100 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure and the crude product waspurified using silica gel column chromatography (2% MeOH-DCM) to givetert-butyl((1r,4r)-4-(12-phenyl-2,5,8,11-tetraoxadodecyl)cyclohexyl)carbamate as ayellow oil (0.7 g, 28%). LC-MS (ESI⁺) m/z 452.5 (M+H)⁺.

Step 2—Tert-Butyl((1R,4R)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1R,4R)-4-(12-phenyl-2,5,8,11-tetraoxadodecyl)cyclohexyl)carbamate(0.85 g, 1.88 mmol) in ethanol (25 mL) and acetic acid (0.3 mL) wasadded 10% Pd/C (0.85 g, wet) at rt under nitrogen atmosphere. Theresulting reaction mixture was then stirred under hydrogen gas (2 kg/cm²pressure) in autoclave at rt for 1.5 h. The reaction mixture wasfiltered through a pad of celite under vacuum and washed with MeOH (50mL). The filtrate was evaporated under reduced pressure to givetert-butyl((1R,4R)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamateas a yellow oil (0.65 g, 95%). LC-MS (ESI⁺) m/z 362.4 (M+H)⁺.

Step3—2-(2-(2-(((1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)ethoxy)ethoxy)ethylMethanesulfonate

To a stirred solution of tert-butyl((1R,4R)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate(0.65 g, 1.8 mmol) and TEA (0.8 mL, 5.4 mmol) in DCM (10 mL) was addedmesyl chloride (0.21 mL, 2.7 mmol) dropwise at 0° C. The resultingreaction mixture was allowed to warm to rt for 1 h. The reaction mixturewas then transferred into water and the resulting mixture was extractedusing DCM (3×100 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to give2-(2-(2-(((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)ethoxy)ethoxy)ethylmethanesulfonate as a brown oil (0.75 g, 95%). LC-MS (ESI⁺) m/z 440.5(M+H)⁺.

Step 4—Tert-Butyl((1R,4R)-4-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate

To a stirred solution of2-(2-(2-(((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methoxy)ethoxy)ethoxy)ethylmethanesulfonate (0.75 g, 1.71 mmol) in DMF (10 mL) was added sodiumazide (0.17 g, 2.55 mmol) at rt. The resulting reaction mixture was thenheated to 65° C. and stirred for 2 h. The reaction mixture was thentransferred into water and the resulting mixture was extracted usingethyl acetate (3×100 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was then evaporatedunder reduced pressure and the crude product was purified using silicagel column chromatography (35% EtOAc-Hexanes) to give tert-butyl((1R,4R)-4-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamateas a colorless oil (0.55 g, 83%). LC-MS (ESI⁺) m/z 387.4 (M+H)⁺.

Step 5—Tert-Butyl((1R,4R)-4-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1R,4R)-4-((2-(2-(2-azidoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamate(0.55 g, 1.42 mmol) in ethanol (15 mL) was added 10% Pd/C (0.55 g, wet)at rt under nitrogen atmosphere. The resulting reaction mixture was thenstirred under hydrogen gas (15 kg/cm² pressure) in autoclave at rt for 5h. The reaction mixture was filtered through a pad of celite undervacuum and washed with MeOH (50 mL). The filtrate was evaporated underreduced pressure to give tert-butyl((1R,4R)-4-((2-(2-(2-aminoethoxy)ethoxy)ethoxy)methyl)cyclohexyl)carbamateas a yellow oil (0.45 g, 88%). LC-MS (ESI⁺) m/z 361.45 (M+H)⁺.

1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl 4-methylbenzenesulfonate(Intermediate X)

Step 1—1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol

To a stirred solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (10 g,42 mmol, CAS #4792-15-8) in THF (50 mL) was added 60% NaH in paraffin(0.84 g, 21 mmol) at 10° C. The resulting reaction mixture was stirredat the same temperature for 0.5 h. To this reaction mixture benzylbromide (3.6 g, 21 mmol) in THF (50) was added dropwise at 10° C. over1.5 h. The resulting reaction mixture was allowed warm to rt and stirredfor 16 h. The reaction mixture was then transferred into ice water andthe resulting mixture was extracted using ethyl acetate (3×100 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure and thecrude product was purified using silica gel column chromatography (3%MeOH-DCM) to give 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol as ayellow oil (6 g, 43%). LC-MS (ESI⁺) m/z 347.4 (M+H₂O)⁺.

Step 2—1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl4-methylbenzenesulfonate

To a stirred solution of methyl1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol (6.0 g, 18.2 mmol) and TEA(8 mL, 55 mmol) in DCM (150 mL) was added tosyl chloride (5.2 g, 27.3mmol) at rt. The resulting reaction mixture then stirred at rt for 16 h.The reaction mixture was then transferred into ice water and theresulting mixture was extracted using DCM (3×100 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure and the crude product waspurified using silica gel column chromatography (2% MeOH-DCM) to give1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl 4-methylbenzenesulfonate asa yellow oil (7 g, 79%). LC-MS (ESI⁺) m/z 484.2 (M+H)⁺.

Tert-Butyl((1R,4R)-4-(16-amino-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamate(Intermediate Y)

Step 1—Tert-Butyl((1R,4R)-4-(18-phenyl-2,5,8,11,14,17-hexaoxaoctadecyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1R,4R)-4-(hydroxymethyl)cyclohexyl)carbamate (1.5 g, 0.7 mmol,synthesized via Steps 1-2 of Intermediate K) and1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-yl 4-methylbenzenesulfonate(4.74 g, 0.98 mmol, Intermediate X) in THF (30 mL) was added KOH (3.67g, 65.4 mmol) at rt. The resulting reaction mixture then heated to 60°C. and stirred for 16 h. The reaction mixture was then transferred intoice water and the resulting mixture was extracted using ethyl acetate(3×100 mL). The combined organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the crude product was purified using silica gel columnchromatography (2% MeOH-DCM) to give tert-butyl((1R,4R)-4-(18-phenyl-2,5,8,11,14,17-hexaoxaoctadecyl)cyclohexyl)carbamateas a yellow oil (0.92 g, 26%). LC-MS (ESI⁺) m/z 557.4 (M+18)⁺.

Step 2—Tert-Butyl((1R,4R)-4-(16-hydroxy-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1R,4R)-4-(18-phenyl-2,5,8,11,14,17-hexaoxaoctadecyl)cyclohexyl)carbamate(0.91 g, 1.68 mmol) in ethanol (15 mL) was added 10% Pd/C (0.9 g, 50%wet) at rt under nitrogen atmosphere. The resulting reaction mixture wasstirred under hydrogen gas (2 kg/cm² pressure) in an autoclave at rt for6 h. The reaction mixture was filtered through a pad of celite undervacuum and washed with MeOH (50 mL). The filtrate was evaporated underreduced pressure to give tert-butyl((1R,4R)-4-(16-hydroxy-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamateas a yellow oil (0.75 g, 99%). LC-MS (ESI⁺) m/z 450.2 (M+H)⁺.

Step3—1-((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,11,14-pentaoxahexadecan-16-ylMethanesulfonate

To a stirred solution of tert-butyl((1R,4R)-4-(16-hydroxy-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamate(0.8 g, 1.8 mmol) and TEA (0.75 mL, 5.33 mmol) in DCM (10 mL) was addedmesyl chloride (0.2 mL, 2.66 mmol) dropwise at 0° C. The resultingreaction mixture was allowed to warm to rt and stirred for 1 h. Thereaction mixture was then transferred into water and the resultingmixture was extracted using DCM (3×100 mL). The combined organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure to give1-((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,11,14-pentaoxahexadecan-16-ylmethanesulfonate as a brown oil (0.9 g, 96%). LC-MS (ESI⁺) m/z 545.6(M+18)⁺.

Step 4—Tert-Butyl((1R,4R)-4-(16-azido-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamate

To a stirred solution of1-((1R,4R)-4-((tert-butoxycarbonyl)amino)cyclohexyl)-2,5,8,11,14-pentaoxahexadecan-16-ylmethanesulfonate (0.9 g, 1.7 mmol) in DMF (10 mL) was added sodium azide(0.17 g, 2.55 mmol) at rt. The resulting reaction mixture was thenheated to 65° C. and stirred for 2 h. The reaction mixture was thentransferred into water and the resulting mixture was extracted usingethyl acetate (3×100 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the crude product was purified using silica gelcolumn chromatography (45% EAc-Hexanes) to give tert-butyl((1R,4R)-4-(16-azido-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamateas a colorless oil (0.72 g, 90%).

Step 5—Tert-Butyl((1R,4R)-4-(16-amino-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamate

To a stirred solution of tert-butyl((1R,4R)-4-(16-azido-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamate(0.7 g, 1.47 mmol) in ethanol (20 mL) was added 10% Pd/C (0.7 g, 50%wet) at rt under nitrogen atmosphere. The resulting reaction mixture wasthen stirred under hydrogen gas (15 kg/cm² pressure) in an autoclave atrt for 4 h. The reaction mixture was then filtered through a pad ofcelite under vacuum and washed with MeOH (50 mL). The filtrate wasevaporated under reduced pressure to give tert-butyl((1R,4R)-4-(16-amino-2,5,8,11,14-pentaoxahexadecyl)cyclohexyl)carbamateas a yellow oil (0.52 g, 78%). LC-MS (ESI⁺) m/z 449.5 (M+H)⁺.

4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride (Intermediate Z)

Step 1—Tert-Butyl(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.95 g, 3.44mmol, Intermediate R) and DABCO (0.5 g, 4.5 mmol) in DMF (25 mL) wasadded tert-butyl (14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (1.5 g,4.5 mmol, CAS #811442-84-9) at rt. The resulting reaction mixture thenheated at 80° C. for 3 h. The reaction mixture was then transferred intoice water and the resulting mixture was extracted using ethyl acetate(3×50 mL). The combined organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the crude product was purified using silica gel columnchromatography (2% MeOH-DCM) to give tert-butyl(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamateas a yellow oil (0.35 g, 17%). LCMS (ESI⁺) m/z 593.6 (M+H)⁺.

Step2—4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride

To a stirred solution of tert-butyl(14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamate(0.35 g, 0.59 mmol) in 1,4 dioxane (10 mL) was added 4 M HCl in dioxane(10 mL) at 0° C. The resulting reaction mixture was allowed to warm tort and stirred for 16 h. The reaction mixture was then evaporated undervacuum and triturated using MTBE to give4-((14-amino-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride as a yellow solid (0.28 g, 90%). LCMS (ESI⁺) m/z 493.45(M+H)⁺.

Tert-Butyl 6-bromohexanoate (Intermediate AA)

Step 1—6-bromohexanoyl Chloride

To a stirred solution of 6-bromohexanoic acid (5.0 g, 25.6 mmol) and DMF(catalytic amount) in DCM (50 mL) was added oxalyl chloride (2.5 mL,28.16 mmol) dropwise at 0° C. The resulting reaction mixture was thenwarmed to rt and stirred for 16 h. The reaction mixture was thenevaporated under reduced pressure to give 6-bromohexanoyl chloride as abrown oil (5 g, 91%).

Step 2—Tert-Butyl 6-bromohexanoate

To a stirred solution of 6-bromohexanoyl chloride (5.5 g, 25.8 mmol) andpyridine (2.55 mL, 30.9 mmol) in DCM (50 mL) was added tert-butanol(3.71 mL g, 38.62 mmol) dropwise at rt. The resulting reaction mixturestirred at rt for 16 h. The reaction mixture was then transferred intoice water and the resulting mixture was extracted using DCM (3×100 mL).The combined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure and thecrude product was purified using silica gel column chromatography (6%EAc-Hexanes) to give tert-butyl 6-bromohexanoate as a colorless oil (4.5g, 70%). ¹H NMR (400 MHz, DMSO) δ 3.43 (t, J=8 Hz, 2H), 2.25 (t, J=7.2Hz, 2H), 1.93-1.86 (m, 2H), 1.67-1.60 (m, 2H), 1.52-1.50 (m, 2H), 1.46(s, 9H).

Tert-Butyl 6-((7-aminoheptyl)oxy)hexanoate (Intermediate AB)

Step 1: 7-azidoheptan-1-ol

To a stirred solution of 7-bromoheptan-1-ol (0.5 g, 2.6 mmol) and TBAB(0.083 g, 0.25 mmol) in toluene (10 mL) was added sodium azide (0.35 g,5.12 mmol) at rt. The resulting reaction mixture was then heated to 90°C. and stirred for 16 h. The reaction mixture was then filtered throughcelite, washed with DCM (25 mL), and filtrate was evaporated underreduced pressure. The crude product was purified using silica gel columnchromatography (10% EAc-Hexanes) to give 7-azidoheptan-1-ol as acolorless oil (0.35 g, 87%). LC-MS (ESI+) m/z 157.2 (M+H)⁺.

Step 2—Tert-Butyl 6-((7-azidoheptyl)oxy)hexanoate

To a stirred solution of 7-azidoheptan-1-ol (1.1 g, 7.2 mmol) in DMF (30mL) was added NaI (0.18 g, 1.19 mmol) and 60% NaH (0.36 g, 8.9 mmol) atrt. The resulting reaction mixture was stirred at rt for 0.5 h thentert-butyl 6-bromohexanoate (1.5 g, 5.97 mmol) in DMF (5 mL) was addeddropwise at rt. The resulting reaction mixture then heated to 50° C. andstirred for 16 h. The reaction mixture was then transferred into icewater and the resulting mixture was extracted using ethyl acetate (3×100mL). The combined organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was evaporated under reduced pressure and thecrude product was purified using silica gel column chromatography (3%EAc-Hexanes) to give tert-butyl 6-((7-azidoheptyl)oxy)hexanoate as acolorless oil (0.3 g, 10%). ¹H NMR (400 MHz, DMSO) δ 3.43-3.39 (m, 4H),3.27 (t, J=7.2 Hz, 2H), 2.23 (t, J=7.6 Hz, 2H), 1.66-1.48 (m, 8H), 1.46(m, 9H), 1.44-1.41 (m, 8H).

Step 3—Tert-Butyl 6-((7-aminoheptyl)oxy)hexanoate

To a stirred solution of tert-butyl 6-((7-azidoheptyl)oxy)hexanoate (0.3g, 0.92 mmol) in methanol (30 mL) was added 20% Pd(OH)₂ (0.3 g) at rtunder nitrogen atmosphere. The resulting reaction mixture then stirredunder hydrogen gas (20 kg/cm² pressure) in an autoclave at rt for 4 h.The reaction mixture was then filtered through a pad of celite undervacuum and washed with MeOH (50 mL). The filtrate was then evaporatedunder reduced pressure to give tert-butyl6-((7-aminoheptyl)oxy)hexanoate as a colorless oil (0.25 g, 90%). ¹H NMR(400 MHz, DMSO) δ 3.42-3.38 (m, 4H), 2.69 (t, J=7.2 Hz, 2H), 2.23 (t,J=7.6 Hz, 2H), 1.65-1.56 (m, 8H), 1.46 (m, 10H), 1.42-1.33 (m, 8H).

Tert-Butyl(2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate(Intermediate AC)

Step 1—Tert-Butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate

A solution of 2-(2-(2-aminoethoxy)ethoxy)ethan-1-ol (1.5 g, 10.1 mmol),triethylamine (3.3 mL, 15.1 mmol), and Boc-anhydride (3.3 g, 15.1 mmol)in DCM (10 mL) was stirred at rt for 2 h. The reaction mixture was thentransferred into ice water and the resulting mixture was extracted usingDCM (3×25 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure and the crude product was purified using silica gel columnchromatography (3% MeOH-DCM) to give tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate as a colorless oil (1.8 g,72%). LC-MS (ESI⁺) m/z 267.35 (M+H)⁺.

Step 2—2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-ylmethanesulfonate

To a stirred solution oftert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.8 g, 7.2mmol) and triethylamine (3.0 g, 4.15 mL, 21.7 mmol) in DCM (12 mL) wasadded of mesyl chloride (0.85 g, 10.8 mmol) and the reaction mixture wasstirred at rt for 2 h. The reaction mixture was then transferred intoice water and the resulting mixture was extracted using DCM (3×25 mL).The combined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to give2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl methanesulfonate asa yellow semisolid (2.2 g, 93%).

Step 3—Tert-Butyl (2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate

A stirred solution oftert-butyl(2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate (2.0 g,6.1 mmol), 2M Methyl amine in THF (36.66 mL, 73.32 mmol) and DIPEA (3mL, 3 eq) in DMF (20 mL) was heated at 90° C. for 10 h. The reactionmixture was then transferred into ice water and the resulting mixturewas extracted using ethyl acetate (3×25 mL). The combined organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure to give tert-butyl(2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate (1.2 g, 68%).

2-azidoethan-1-ol (Intermediate AD)

To a stirred solution of 2-bromoethan-1-ol (10 g, 80 mmol) in water (100mL) was added sodium azide (10.4 g, 160.1 mmol) and the reaction mixturewas heated at 80° C. for 16 h. The reaction mixture was then extractedusing diethyl ether (250 mL×3), dried over anhydrous sodium sulphate andevaporated in vacuum to give 2-azidoethan-1-ol as a light yellow oil(6.5 g, 93%); ¹H NMR (400 MHz, DMSO) δ 5.00 (t, J=5.2 Hz, 1H), 3.7-3.5(m, 2H), 3.3-3.2 (m, 2H).

2-azidoethyl 4-methylbenzenesulfonate (Intermediate AE)

To a stirred mixture of 2-azidoethan-1-ol (0.1 g, 1.2 mmol, IntermediateAD) in DCM (5 mL) was added TEA (0.5 mL, 3.5 mmol) and TsCl (0.286 g,1.5 mmol) at 0° C. and the reaction mixture was stirred for 3 h. Thereaction mixture was then diluted with water (100 mL) and extractedusing DCM (50 mL×3). The combined organic layer was dried over anhydroussodium sulphate, filtered and evaporated in vacuo and the crude productwas purified by silica gel column chromatography (10-15% EtOAc-Hexane)to give 2-azidoethyl 4-methylbenzenesulfonate as a colorless semisolid(0.15 g, 54%). ¹H NMR (400 MHz, DMSO) δ 7.83 (d, J=8.4 Hz, 2H), 7.52 (d,J=8.0 Hz, 2H), 4.17 (t, J=4.8 Hz, 2H), 3.56 (t, J=4.8 Hz, 2H), 2.52 (d,J=1.6 Hz, 2H).

Tert-Butyl (2-((6-((2-aminoethoxy)methyl)pyridin-3-yl)methoxy)ethyl)carbamate (Intermediate AF)

Step 1—Methyl 6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)nicotinate

To a stirred solution of methyl 6-(hydroxymethyl)nicotinate (0.5 g, 3.0mmol) in DCM (50 mL), was added p-TsOH (0.63 g, 3.3 mmol) at 0° C.followed by 3,4-dihydro-2H-pyran (0.9 mL, 9.0 mmol) at same temperature.The mixture was allowed to warm to rt then stirred for 16 h. Thereaction mixture was diluted with water (50 mL) and product wasextracted using DCM (50 mL×3). The combined organic layer was dried overanhydrous sodium sulphate and vacuum evaporated and the crude productwas purified by silica gel column chromatography (0-1% MeOH-DCM to givemethyl 6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)nicotinate as a yellowsemisolid (0.7 g, 90%); LC-MS (ESI⁺) m/z 252.3 (M+H)⁺.

Step 2—(6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)methanol

To a stirred solution of methyl6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)nicotinate (0.7 g, 2.79 mmol)in THF (25 mL) was added 1M lithium aluminum hydride in THF (7 mL, 7mmol) dropwise at −70° C. and the mixture was stirred for 30 minutes atthe same temperature. The reaction mixture was then quenched with water(100 mL), filtered through celite and the filtrate was extracted inethyl acetate (100 mL×3). The combined organic layer was dried overanhydrous sodium sulphate, filtered and evaporated in vacuo and thecrude product was purified by silica gel column chromatography (70-80%EtOAc-Hexane) to give(6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)methanol as ayellow semisolid (0.3 g, 48%); LC-MS (ESI⁺) m/z 224.25 (M+H)⁺.

Step 3—5-(bromomethyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine

To a stirred solution of(6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)methanol (0.3 g,1.34 mmol) in DCM (10 mL) was added carbon tetrabromide (0.668 g, 2.02mmol) and triphenylphosphine (0.334 g, 1.47 mmol) at 0° C. and thereaction mixture was stirred for 4 h. The reaction mixture was thendiluted with water (50 mL) and product was extracted using DCM (50mL×3). The combined organic layer was dried over anhydrous sodiumsulphate, filtered and evaporated in vacuo. The crude product waspurified by silica gel column chromatography (50% EtOAc-Hexane) to give5-(bromomethyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine as ayellow oil (0.05 g, 13%); LC-MS (ESI⁺) m/z 288.2 (M+H)⁺.

Step4—5-((2-azidoethoxy)methyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine

To a stirred solution of 2-azidoethan-1-ol (0.8 g, 9.1 mmol,Intermediate AD) in DMF (10 mL) was added 60% NaH in oil (0.363 g, 9.09mmol) at 0° C. followed by addition of a solution of5-(bromomethyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine (1.3g, 4.54 mmol) in DMF (5 mL) and the reaction was stirred for 15 min. Thereaction mixture was then quenched with water (50 mL) and product wasextracted in ethyl acetate (250 mL). The organic layer was washed withwater (250 mL×3) and dried over anhydrous sodium sulphate, filtered andevaporated in vacuo. The crude product was purified by silica gel columnchromatography (50% EtOAc-Hexane) to give5-((2-azidoethoxy)methyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridineas a yellow oil (1.1 g, 83%); LC-MS (ESI⁺) m/z 293.3 (M+H)⁺.

Step 5—(5-((2-azidoethoxy)methyl)pyridin-2-yl)methanol

To a stirred solution of5-((2-azidoethoxy)methyl)-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine(1.1 g, 3.8 mmol) in methanol (25 mL) was added p-TsOH (0.648 g, 3.76mmol) at 0° C. and the reaction mixture was allowed to warm to rt andstirred for 16 h. The reaction mixture was then concentrated, dilutedwith water (250 mL) and extracted in ethyl acetate (200 mL×3). Thecombined organic layer was dried over anhydrous sodium sulphate,filtered and evaporated in vacuo. The crude product was purified bysilica gel column chromatography u (10% MeOH-DCM) to give(5-((2-azidoethoxy)methyl)pyridin-2-yl)methanol as a yellow semisolid(0.55 g, 70%); LC-MS (ESI⁺) m/z 209.2 (M+H)⁺.

Step 6—Tert-Butyl(2-((6-(hydroxymethyl)pyridin-3-yl)methoxy)ethyl)carbamate

To a stirred solution of (5-((2-azidoethoxy)methyl)pyridin-2-yl)methanol(0.55 g, 2.64 mmol) in ethanol (50 mL) was added Boc anhydride (0.91 mL,3.96 mmol) and 20% Pd(OH)₂/C (50% wet) (0.55 g) in autoclave at rt underhydrogen gas (20 kg/cm² pressure) and the reaction was stirred for 6 h.The reaction mixture was then filtered through celite and the filtratewas concentrated in vacuo. The crude product was purified by silica gelcolumn chromatography (70-80% EtOAc-Hexane) to give tert-butyl(2-((6-(hydroxymethyl)pyridin-3-yl)methoxy)ethyl)carbamate as a yellowsemisolid (0.4 g, 54%); LC-MS (ESI⁺) m/z 283.3 (M+H)⁺.

Step 7—Tert-Butyl(2-((6-((2-azidoethoxy)methyl)pyridin-3-yl)methoxy)ethyl)carbamate

To a stirred solution of tert-butyl(2-((6-(hydroxymethyl)pyridin-3-yl)methoxy)ethyl)carbamate (0.15 g, 0.53mmol), 8N NaOH in water (2 mL) and TBAB in toluene (2 mL) was added2-azidoethyl 4-methylbenzenesulfonate (3 mL, 18 mmols, Intermediate AE)and the mixture was refluxed for 48 h. The reaction mixture was thendiluted with water (100 mL) and extracted using ethyl acetate (50 mL×3).The combined organic layer was dried over anhydrous sodium sulphate,filtered and evaporated in vacuo. The crude product was purified bysilica gel column chromatography (2% MeOH-DCM) to give tert-butyl(2-((6-((2-azidoethoxy)methyl)pyridin-3-yl)methoxy)ethyl)carbamate as acolorless oil (0.065 g, 35%); LC-MS (ESI⁺) m/z 352.3 (M+H)⁺.

Step 8—Tert-Butyl(2-((6-((2-aminoethoxy)methyl)pyridin-3-yl)methoxy)ethyl) carbamate

To a stirred solution of tert-butyl(2-((6-((2-azidoethoxy)methyl)pyridin-3-yl)methoxy)ethyl)carbamate(0.145 g) in ethanol (10 mL) was added 20% Pd(OH)₂/C (50% wet) (0.14 g)in an autoclave at rt and the reaction mixture was stirred underhydrogen gas (20 kg/cm² pressure) for 4 h. The reaction mixture was thenfiltered through celite and the filtrate was concentrated and evaporatedin vacuo to give tert-butyl(2-((6-((2-aminoethoxy)methyl)pyridin-3-yl)methoxy)ethyl)carbamate as ayellow semisolid (0.1 g, 74%); LC-MS (ESI⁺) m/z 326.5 (M+H)⁺.

(1R,4R)-4-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicAcid (Intermediate AG)

Step 1—Methyl(1R,4R)-4-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylate

A stirred solution of6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinicacid (0.3 g, 0.94 mmol, Intermediate L), methyl(1R,4R)-4-aminocyclohexane-1-carboxylate hydrochloride (0.18 g, 0.94mmol), HATU (0.54 g, 1.41 mmol) and DIPEA (0.54 mL, 1.41 mmol) in DMF (5mL) was stirred at rt for 4 h. The reaction mixture was transferred theninto ice water and the resulting precipitate was filtered off and driedunder vacuum to give methyl(1R,4R)-4-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylateas an off white solid (0.38 g, 88%). LC-MS (ESI⁺) m/z 460.2 (M+H)⁺.

Step2—(1R,4R)-4-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicAcid

To a stirred solution of methyl(1r,4r)-4-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylate(0.38 g, 0.82 mmol) in THF:water (1:1, 10 mL) was added lithiumhydroxide monohydrate (0.11 g, 2.48 mmol) at rt and the reaction mixturewas stirred for 2 h. The reaction mixture was then transferred into icewater and the pH was adjusted to 5-6 using 10% citric acid solution. Theresulting precipitate was filtered off and dried under vacuum to give(1R,4R)-4-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicacid as an off-white solid (0.25 g, 76%). LC-MS (ESI⁺) m/z 446.4 (M+H)⁺.

3-(Dibenzylamino)-2-Fluoro-Propan-1-Ol (Intermediate Ah)

Step 1—Methyl 2-(dibenzylamino)-3-hydroxy-propanoate

To a mixture of methyl 2-amino-3-hydroxy-propanoate (15.0 g, 96.4 mmol,HCl salt) and benzyl bromide (36.3 g, 212 mmol, 25.2 mL) in acetonitrile(200 mL) was added potassium carbonate (66.6 g, 482 mmol). The mixturewas stirred at rt for 12 h. On completion, the reaction mixture wasfiltered and washed with acetonitrile. The combined organic layers wereconcentrated in vacuo. The residue was purified by column chromatographyto give the title compound (16.1 g, 56% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 7.39-7.28 (m, 8H), 7.27-7.20 (m, 2H), 4.80 (dd,J=4.8, 6.0 Hz, 1H), 3.84-3.80 (m, 2H), 3.69 (s, 3H), 3.56 (d, J=14.4 Hz,2H), 3.40-3.30 (m, 2H); LC-MS (ESI⁺) m/z 300.1 (M+H)⁺.

Step 2—Methyl 3-(dibenzylamino)-2-fluoro-propanoate

To a solution of methyl 2-(dibenzylamino)-3-hydroxy-propanoate (5.00 g,16.7 mmol) in THF (20.0 mL) was added a solution of DAST (3.23 g, 20.0mmol, 2.65 mL) in 10 mL THF. The reaction mixture was stirred at rt for1 h. On completion, the reaction mixture was quenched by the addition ofice-water (50 mL) followed by ethyl acetate (200 mL). The mixture wasrapidly stirred and solid NaHCO₃ was added until effervescence ceased.The layers were then separated and the aqueous layer was extracted withethyl acetate (2×50 mL). The combined organic phase was washed withwater (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by column chromatography togive the title compound (3.63 g, 72% yield) as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.42-7.25 (m, 10H), 5.19-5.01 (m, 1H), 3.88 (d, J=13.6 Hz,2H), 3.77-3.71 (s, 3H), 3.57 (d, J=13.6 Hz, 2H), 3.16-2.96 (m, 2H);LC-MS (ESI⁺) m/z 302.1 (M+H)⁺.

Step 3—3-(Dibenzylamino)-2-fluoro-propan-1-ol

To a solution of lithium borohydride (50.6 mg, 2.3 mmol) in THF (5 mL)was added a solution of methyl 3-(dibenzylamino)-2-fluoro-propanoate(500 mg, 1.66 mmol) in THF (10 mL) at −15° C. under nitrogen. Thereaction was allowed to warm to rt and was stirred for 4 h. Oncompletion, the reaction mixture was quenched with saturated ammoniumchloride solution (10 mL) dropwise, and then extracted with ethylacetate. The combined organic phase was dried over Na₂SO4, filtered andconcentrated in vacuo to give the title compound (2.70 g, 96% yield) asa white oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.28 (m, 10H), 4.76-4.58 (m,1H), 3.82-3.67 (m, 4H), 3.66-3.60 (m, 2H), 3.11-3.08 (m, 1H), 2.90-2.84(m, 2H); LC-MS (ESI⁺) m/z 274.1 (M+H)⁺.

Tert-Butyl(2-(2-(2-(3-amino-2-fluoropropoxy)ethoxy)ethoxy)ethyl)carbamate(Intermediate A1)

Step 1—2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-ylmethanesulfonate

To a solution of tert-butylN-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (4.00 g, 16.0 mmol, CAS#139115-92-7) in dichloromethane (5 mL) was added triethylamine (3.25 g,32.0 mmol) and MsCl (2.21 g, 19.2 mmol) at 0° C. The reaction mixturewas then allowed to warm to rt and stirred for 1. On completion, thereaction mixture was quenched with water (10 mL) and extracted withdichloromethane (3×100 mL). The combined organic layer was washed withbrine (2×50 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound (5.23 g, 99% yield) asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.94 (s, 1H), 4.44-4.37 (m,2H), 3.83-3.75 (m, 2H), 3.69-3.65 (m, 2H), 3.64-3.59 (m, 2H), 3.54 (t,J=5.2 Hz, 2H), 3.36-3.29 (m, 2H), 3.08 (s, 3H), 1.45 (s, 9H).

Step 2—Tert-Butyl(2-benzyl-4-fluoro-1-phenyl-6,9,12-trioxa-2-azatetradecan-14-yl)

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (3.64 g, 13.3mmol, Intermediate AH) in DMF (5 mL) was added sodium hydride (1.60 g,39.5 mmol, 60% oil dispersion) at 0° C. under nitrogen atmosphere. Thereaction mixture was stirred at 0° C. for 1 h. Then,2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methane sulfonate(5.23 g, 15.9 mmol) was added. The resulting reaction mixture wasstirred at rt for 3 h. On completion, the reaction mixture was quenchedwith saturated NH₄Cl (20 mL) and extracted with ethyl acetate (3×100mL). The combined organic layer was washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by reverse phase flash column (0.1% NH₃ H₂O) togive the title compound (2.95 g, 44% yield) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.28 (m, 10H), 5.02 (s, 1H), 4.89-4.70 (m, 1H),3.72-3.61 (m, 12H), 3.60-3.56 (m, 2H), 3.54 (t, J=5.2 Hz, 2H), 3.31-3.18(m, 2H), 2.82-2.69 (m, 2H), 1.46 (s, 9H); LC-MS (ESI)⁺ m/z 505.2.(M+H)⁺.

Step 3—Tert-Butyl(2-(2-(2-(3-amino-2-fluoropropoxy)ethoxy)ethoxy)ethyl)carbamate

To a solution of tert-butylN-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethyl]carbamate (2.90 g, 5.75 mmol) in THF (5 mL) was added Pd(OH)₂/C (1.00 g,10 wt %) and Pd/C (1.00 g, 10 wt %) under nitrogen atmosphere. Thesuspension was degassed and purged with hydrogen gas 3 times. Themixture was then stirred under hydrogen gas (50 psi pressure) at rt for24 h. On completion, the reaction mixture was filtered and concentratedin vacuo to give the title compound (1.70 g, 91% yield) as a white gum.LC-MS (ESI)⁺ m/z 325.1. (M+H)⁺.

BenzylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate AJ)

Step 1—2-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate

To a solution of2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol (3.50 g, 14.7mmol, CAS #4792-15-8) in tetrahydrofuran (30 mL) was added a solution ofsodium hydroxide (763 mg, 19.1 mmol) in water (30 mL) at 0° C. Then asolution of TsCl (2.80 g, 14.7 mmol) in tetrahydrofuran (90 mL) wasadded slowly dropwise at 0° C. The reaction mixture was then allowed towarm to rt and stirred for 12 h. On completion, the reaction mixture wasdiluted with water (100 mL) and extracted with dichloromethane (3×100mL). The combined organic layer was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give the title compound (5.20 g,87% yield) as a yellowish oil. LC-MS (ESI⁺) m/z 393.0 (M+H)⁺.

Step 2—2-[2-[2-[2-(2-Azidoethoxy)ethoxy]ethoxy]ethoxy]ethanol

To a mixture of 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (4.50 g, 11.5 mmol) in DMF (30 mL) was addedsodium azide (1.86 g, 28.6 mmol). Then the reaction mixture was stirredat 80° C. for 12 h. On completion, the reaction mixture was diluted withwater (30 mL) and extracted with a mixture of dichloromethane andmethanol (10:1, 3×30 mL). The organic layer was concentrated in vacuo togive the title compound (3.00 g, 99% yield) as a yellowish oil. LC-MS(ESI⁺) m/z 264.1 (M+H)⁺.

Step 3—2-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]ethanol

To a mixture of 2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethanol(3.00 g, 11.4 mmol) in ethanol (30 mL) was added Pd/C (1.00 g, 11.4mmol, 5 wt %). Then the reaction mixture was stirred at rt for 48 hoursunder hydrogen gas (15 psi pressure). On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (2.70 g, 100% yield) as a yellowish oil. LC-MS (ESI⁺) m/z 238.1(M+H)⁺.

Step 4—BenzylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of 2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethanol(1.20 g, 5.06 mmol) in acetonitrile (10 mL) and water (10 mL) was addedsodium bicarbonate (1.27 g, 15.1 mmol) and CbzCl (1.04 g, 6.07 mmol).Then the reaction mixture was stirred at 25° C. for 12 h. On completion,the reaction mixture was diluted with water (100 mL) and extracted withethyl acetate (3×100 mL). Then the organic layer was dried over Na₂SO₄and concentrated in vacuo. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=1:1) to give the titlecompound (1.50 g, 70% yield) as white solid. LC-MS (ESI⁺) m/z 372.1(M+H)⁺.

Tert-ButylN-[2-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (Intermediate AK)

Step 1—Tert-butylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of benzylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(3.40 g, 9.15 mmol, Intermediate AJ) in ethyl acetate (35.0 mL) wasadded Pd(OH)₂/C (1.00 g, 10 wt %) and (Boc)₂O (3.00 g, 13.7 mmol, 3.15mL). The reaction mixture was stirred under hydrogen gas (15 psipressure) at rt for 16 h. On completion, the mixture was filteredthrough a pad of celite and washed with ethyl acetate (2×5 mL). Then thefiltrate was concentrated in vacuo to give a residue. The residue waspurified by column chromatography (DCM:MeOH=20:1) to give the titlecompound (2.45 g, 79% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 5.34 (s, 1H), 3.76-3.70 (m, 2H), 3.70-3.58 (m, 14H), 3.57-3.50 (m,2H), 3.39-3.20 (m, 2H), 1.43 (s, 9H).

Step2—2-[2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate

To a solution of tert-butylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(2.45 g, 7.26 mmol) and triethylamine (1.47 g, 14.5 mmol) in DCM (15.0mL) was added mesyl chloride (998 mg, 8.71 mmol) at 0° C. Then thereaction mixture was allowed to warm to rt and stirred for 1 hr. Oncompletion, the mixture was diluted with water (30 mL), extracted withDCM (3×50 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (2.88 g,95% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.94 (s, 1H),4.34-4.28 (m, 2H), 3.72-3.67 (m, 2H), 3.61-3.54 (m, 12H), 3.47 (t, J=5.2Hz, 2H), 3.28-3.20 (m, 2H), 3.01 (s, 3H), 1.38 (s, 9H).

Step 3—Tert-ButylN-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (0.50 g, 1.83mmol, Intermediate AH) in DMF (5.00 mL) was added sodium hydride (219mg, 5.49 mmol, 60% purity) at 0° C. The mixture was stirred at 0° C. for1 h, then2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate(912 mg, 2.20 mmol) was added to the reaction and the reaction mixturewas allowed to warm to rt and stirred for 16 hrs. On completion, themixture was quenched with water (50 mL) and extracted with ethyl acetate(3×50 mL). The organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The mixture was purified by reverse phasechromatography (0.1% NH₃ H₂O) to give the title compound (0.26 g, 22%yield) as a colorless oil. LC-MS (ESI⁺) m/z 593.4 (M+H)⁺.

Step 4—Tert-ButylN-[2-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]Carbamate

To a solution of tert-butylN-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.66 g, 2.80 mmol) in methanol (8.00 mL)was added Pd(OH)₂/C (0.50 g, 10 wt %) and Pd/C (0.50 g, 10 wt %) undernitrogen atmosphere. The suspension was degassed and purged withhydrogen gas 3 times. The mixture was stirred under hydrogen (50 psipressure) at rt for 16 h. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give the title compound (0.80 g,69% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.06 (s, 1H),4.63-4.43 (m, 1H), 3.66-3.54 (m, 18H), 3.47 (t, J=5.2 Hz, 2H), 3.28-3.19(m, 2H), 2.93-2.83 (m, 2H), 1.37 (s, 9H).

4-(Dibenzylamino)-3-fluoro-butan-2-ol (Intermediate AL)

Step 1—3-(Dibenzylamino)-2-fluoro-propanoic Acid

To a mixture of methyl 3-(dibenzylamino)-2-fluoro-propanoate (15.0 g,49.7 mmol, synthesized via Steps 1-2 of Intermediate AH) in THF (150 mL)and water (50 mL) was added LiOH H₂O (4.18 g, 99.5 mmol). The reactionmixture was stirred at rt for 12 h. On completion, the reaction mixturewas acidified with HCl (2 M) until the pH=5˜6 and concentrated in vacuoto give a residue. The residue was purified by reverse phasechromatography (0.1% FA condition) to give the title compound (13.4 g,92% yield) as a light yellow gum. LC-MS (ESI⁺) m/z 288.0 (M+H)⁺.

Step 2—3-(Dibenzylamino)-2-fluoro-N-methoxy-N-methyl-propanamide

To a mixture of N-methoxymethanamine (9.10 g, 93.2 mmol, HCl salt) inDMF (150 mL) was added DIPEA (36.1 g, 279 mmol), then3-(dibenzylamino)-2-fluoro-propanoic acid (13.4 g, 46.6 mmol) and HATU(35.4 g, 93.2 mmol). The reaction mixture was stirred at rt for 2.5 hrs.On completion, the reaction mixture was concentrated in vacuo. Theresidue was diluted with water (100 mL) and extracted with ethyl acetate(3×100 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo to give a residue. The residue was purified bycolumn chromatography to give the title compound (15.0 g, 94% yield) asa light yellow oil. LC-MS (ESI⁺) m/z 331.1 (M+H)⁺.

Step 3—4-(Dibenzylamino)-3-fluoro-butan-2-one

To a mixture of3-(dibenzylamino)-2-fluoro-N-methoxy-N-methyl-propanamide (7.00 g, 21.1mmol) in THF (80 mL) was added methyl magnesium bromide (3 M, 21.1 mL,63.3 mmol) at 0° C. The reaction mixture was then warmed to rt andstirred for 2 h. On completion, the reaction mixture was quenched withslow addition of saturated ammonium chloride solution (30 mL) understirring. The reaction mixture was then poured into 3 mL of water andextracted with ethyl acetate (3×80 mL). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by column chromatography to give the titlecompound (4.40 g, 72% yield) as a light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 7.29-7.15 (m, 10H), 4.93-4.77 (m, 1H), 3.72 (d, J=13.6 Hz, 2H),3.49 (d, J=13.6 Hz, 2H), 2.95-2.84 (m, 2H), 2.02 (d, J=4.0 Hz, 3H);LC-MS (ESI⁺) m/z 286.1 (M+H)⁺.

Step 4—4-(Dibenzylamino)-3-fluoro-butan-2-ol

To a mixture of 4-(dibenzylamino)-3-fluoro-butan-2-one (4.40 g, 15.4mmol) in THF (40 mL) and methanol (20 mL) was added sodium borohydride(1.17 g, 30.8 mmol) at 0° C. The reaction mixture was then allowed towarm to rt and stirred for 1 hour. On completion, the reaction mixturewas quenched with slow addition of sat. NH₄Cl solution (4 mL) understirring. The reaction mixture was concentrated in vacuo. The residuewas then poured into (5 mL) of water and extracted with ethyl acetate(3×10 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo to give the title compound (4.30 g, 93% yield)as a colorless oil. LC-MS (ESI⁺) m/z 288.1 (M+H)⁺.

Tert-ButylN-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethyl]carbamate(Intermediate AM)

Step 1—2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethylmethanesulfonate

To a mixture of tert-butylN-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (2.00 g, 8.02 mmol, CAS#139115-92-7) and triethylamine (2.44 g, 24.0 mmol) in DCM (20 mL) wasadded mesyl chloride (1.10 g, 9.63 mmol) at 0° C. The reaction mixturewas then allowed to warm to rt and stirred for 2 h. On completion, thereaction mixture was poured into water (15 mL) and extracted with DCM(3×20 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo to give the title compound (2.60 g, 98% yield)as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.87 (s, 1H), 4.35-4.29(m, 2H), 3.73-3.66 (s, 2H), 3.63-3.52 (m, 4H), 3.50-3.43 (m, 2H),3.30-3.20 (s, 2H), 3.01 (s, 3H), 1.38 (s, 9H).

Step 2—Tert-ButylN-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of 4-(dibenzylamino)-3-fluoro-butan-2-ol (1.60 g, 5.57mmol, Intermediate AL) in DMF (20 mL) was added sodium hydride (668 mg,16.7 mmol, 60% oil dispersion) at 0° C. and the reaction was stirred for0.5 h. Then 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethylmethanesulfonate (2.60 g, 7.94 mmol) was added. The reaction mixture wasallowed to warm to rt and stirred C for 2 h. On completion, the reactionmixture was quenched with slow addition of water (3 mL) under stirring.The reaction mixture was then poured into water (20 mL) and extractedwith ethyl acetate (4×20 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% NH₃ H₂O condition) to givethe title compound (1.25 g, 41% yield) as a light yellow oil. LC-MS(ESI⁺) m/z 519.3 (M+H)⁺.

Step 3—Tert-butylN-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethyl]carbamate (1.30 g, 2.51 mmol) in MeOH (10 mL) was added Pd(OH)₂/C(470 mg, 10 wt %) and Pd/C (470 mg, 10 wt %) under hydrogen atmosphere(15 psi pressure). The reaction mixture was stirred at rt for 14 h. Oncompletion, the reaction mixture was filtered through a pad of celiteand the filtrate was concentrated in vacuo to give the title compound(820 mg, 96% yield) as a colorless oil. LC-MS (ESI⁺) m/z 339.3 (M+H)⁺.

2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol (IntermediateAN)

Step 1—4-(Dibenzylamino)-3-fluoro-2-methyl-butan-2-ol

To a mixture of methyl 3-(dibenzylamino)-2-fluoro-propanoate (15.0 g,49.7 mmol, synthesized via Steps 1-2 of Intermediate AH) in THF (250 mL)was added MeMgBr (3 M, 41.4 mL) dropwise at 0° C. under nitrogenatmosphere. The reaction mixture was stirred at rt for 1 h. Oncompletion, the reaction mixture was quenched with saturated aqueousammonium chloride (10 mL) at 0° C. and extracted with ethyl acetate(2×50 mL). The organic layers were collected, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the titlecompound (15.0 g, 89% yield) as a yellow solid. LC-MS (ESI⁺) m/z 302.1(M+H)⁺.

Step 2—Ethyl 2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetate

To a solution of 4-(dibenzylamino)-3-fluoro-2-methyl-butan-2-ol (30.0 g,99.5 mmol) in DCM (200 mL) was added Rh(OAc)₂ (440 mg, 1.99 mmol) thenethyl 2-diazoacetate (34.0 g, 298 mmol) in DCM (100 mL) was added. Thereaction mixture was stirred at rt for 12 h. On completion, the reactionmixture was concentrated in vacuo. The residue was purified by silicagel chromatography to give the title compound (11.7 g, 28% yield) as acolorless oil. LC-MS (ESI⁺) m/z 388.1 (M+H)⁺

Step 3—2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol

To a solution of ethyl2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetate (8.00 g, 20.6mmol) in THF (220 mL) was added lithium aluminum hydride (1.20 g, 30.9mmol, 98% purity) at 0° C., then reaction mixture was allowed to warm tort and stirred for 3 h. On completion, the reaction mixture was quenchedwith water (2 mL) and NaOH solution (15%, 6 mL) at 0° C. and thereaction mixture was filtered. The filtrate was dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography to give the title compound (5.90g, 81% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.22(m, 10H), 4.64-4.46 (dd, J=7.6, 48.8 Hz, 1H), 3.82 (d, J=13.6 Hz, 2H),3.58 (d, J=13.6 Hz, 2H), 3.53-3.48 (m, 2H), 3.44-3.31 (m, 2H), 2.99-2.82(m, 1H), 2.75-2.61 (m, 1H), 1.72 (s, 1H), 1.13 (s, 3H), 1.09 (s, 3H).

2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylMethanesulfonate (Intermediate AO)

Step 1—2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethyl4-methylbenzenesulfonate

To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (20.0 g,103 mmol, CAS #112-60-7) and potassium iodide (1.71 g, 10.3 mmol) in DCM(2 L) was added 4-methylbenzenesulfonyl chloride (19.6 g, 103 mmol) andsilver oxide (28.6 g, 124 mmol). The reaction mixture was stirred at rtfor 17 h. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (25.1 g, 70% yield) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.83-7.78 (m, 2H), 7.37-7.33 (m,2H), 4.19-4.14 (m, 2H), 3.74-3.60 (m, 14H), 2.45 (s, 3H); LC-MS (ESI⁺)m/z 349.0 (M+H)⁺.

Step 2—2-[2-[2-(2-Azidoethoxy)ethoxy]ethoxy]ethanol

To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (13.5 g, 38.8 mmol) in DMF (100 mL) was addedsodium azide (5.04 g, 77.5 mmol) slowly. The reaction mixture wasstirred at 80° C. for 18 h. On completion, the reaction mixture wasconcentrated in vacuo. The residue was diluted with ethyl acetate (200ml), filtered and the filtrate was concentrated in vacuo to a halfvolume (50 mL). The crude product ethyl acetate solution was used innext step directly.

Step 3—Tert-ButylN-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate

To a solution of 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol (15.0 g,68.4 mmol) and (Boc)₂O (74.7 g, 342 mmol) in ethyl acetate (300 mL) wasadded Pd/C (5 g, 10 wt %) under nitrogen atmosphere. The suspension wasdegassed and purged with hydrogen gas three times. The reaction mixturewas stirred under hydrogen gas (15 Psi pressure) at rt for 18 h. Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo. The residue was purified by silica gel chromatography (SiO₂,DCM/MeOH=10/1) to give the title compound (5.1 g, 25% yield) as a lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.67 (s, 1H), 3.78-3.72 (m, 4H),3.69-3.63 (m, 8H), 3.55 (t, J=4.8 Hz, 2H), 3.34 (d, J=4.8 Hz, 2H), 3.07(s, 1H), 1.46 (s, 9H).

Step 4—2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylMethanesulfonate

To a solution of tert-butylN-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (3.0 g, 10.2mmol) and triethylamine (2.07 g, 2.77 mL, 20.5 mmol) in DCM (30 mL) wasadded mesyl chloride (1.41 g, 12.3 mmol) at 0° C. The reaction mixturewas stirred at rt for 17 h. On completion, the mixture was quenched withwater (30 mL) and extracted with DCM (2×30 mL). The organic layer waswashed with sat.NaHCO₃ (40 mL), then washed with brine (40 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (3.6 g, 95% yield) as a light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 5.05 (s, 1H), 4.43-4.39 (m, 2H), 3.82-3.78 (m, 2H), 3.71-3.69(m, 2H), 3.69-3.67 (m, 2H), 3.67-3.62 (m, 4H), 3.56 (t, J=4.8 Hz, 2H),3.34 (q, J=4.8 Hz, 2H), 3.10 (s, 3H), 1.46 (s, 9H).

Tert-ButylN-[2-[2-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate AP)

Step 1—Tert-ButylN-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol (1.50 g, 4.34mmol, Intermediate AN) in DMF (10 mL) was added sodium hydride (521 mg,13.0 mmol, 60% oil dispersion) at 0° C. for 0.5 h. Then the2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (2.42 g, 6.51 mmol, Intermediate AO) was added. Thereaction mixture was allowed to warm to rt and stirred for 6 hours. Oncompletion, the reaction mixture was quenched with slow addition ofwater (10 mL) under stirring. The mixture was extracted with DCM (3×20mL). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byreverse phase chromatography (0.1% NH₃ H₂O condition) to give the titlecompound (1.10 g, 39% yield) as a light yellow oil. LC-MS (ESI⁺) m/z621.5 (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.10 g, 1.77 mmol) in methanol (10mL) was added Pd(OH)₂/C (600 mg, 10 wt %), Pd/C (600 mg, 10 wt %) andNH₃ H₂O (455 mg, 12.9 mmol, 500 uL) under hydrogen atmosphere (15 psipressure). The reaction mixture was stirred at rt for 15 h. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (750 mg, 96% yield) as a light yellow oil.LC-MS (ESI⁺) m/z 441.3 (M+H)⁺.

2-[2-(2-Bromoethoxy)ethyl]isoindoline-1,3-dione (Intermediate AO)

A solution of (1,3-dioxoisoindolin-2-yl)potassium (10.0 g, 53.9 mmol)and 1-bromo-2-(2-bromoethoxy)ethane (37.5 g, 161 mmol) in acetone (250mL) was stirred at 60° C. for 12 h. On completion, the reaction mixturewas filtered and concentrated in vacuo to give a residue. The residuewas purified by column chromatography to give the title compound (12.0g, 74% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91-7.84 (m,2H), 7.77-7.72 (m, 2H), 3.96-3.90 (m, 2H), 3.84-3.77 (m, 4H), 3.42 (t,J=6.0 Hz, 2H).

Tert-butylN-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethyl]carbamate(Intermediate AR)

Step1—2-[2-[2-[2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethyl]isoindoline-1,3-dione

To a solution of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol (2.00 g, 5.79mmol, Intermediate AN) in DMF (35 mL) was added sodium hydride (694 mg,17.3 mmol, 60% oil dispersion) at 0° C. The reaction mixture was stirredat 0° C. for 0.5 h, and then2-[2-(2-bromoethoxy)ethyl]isoindoline-1,3-dione (2.76 g, 9.26 mmol,Intermediate AQ) was added and the reaction mixture was stirred allowedto warm to rt and stirred for 17 h. On completion, the reaction mixturewas quenched with water (1 mL) at 0° C., and then concentrated in vacuoto give the product (5.00 g) as yellow oil. LC-MS (ESI)⁺ m/z 563.2.(M+H)⁺.

Step2—3-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine

To a solution of2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethyl]isoindoline-1,3-dione (5.00 g, 8.89 mmol) in EtOH (40 mL) was addedhydrazine (2.27 g, 44.4 mmol, 98% purity) and the reaction mixture wasstirred at 80° C. for 38 h. On completion, the reaction mixture wasfiltered and the filtrate concentrated in vacuo to give the titlecompound (2.50 g) as a yellow oil. LC-MS (ESI)⁺ m/z 433.1. (M+H)⁺.

Step 3—Tert-ButylN-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine(2.50 g, 5.78 mmol, crude) in DCM (30 mL) was added (Boc)₂O (2.52 g,11.56 mmol) and the reaction mixture was stirred at rt for 3 h. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase chromatography (0.1% NH₃ H₂O) togive the title compound (950 mg, 30% yield) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 7.42 (d, J=7.2 Hz 4H), 7.31 (t, J=7.2 Hz, 4H),7.26-7.19 (m, 2H), 5.01 (s, 1H), 4.64 (dd, J=8.0, 49.2 Hz, 1H), 3.75 (d,J=13.6 Hz, 2H), 3.60 (d, J=13.6 Hz, 2H), 3.57-3.38 (m, 10H), 3.31 (d,J=3.6 Hz, 2H), 2.98-2.80 (m, 1H), 2.79-2.65 (m, 1H), 1.45 (s, 9H), 1.10(d, J=8.8 Hz, 6H); LC-MS (ESI)⁺ m/z 533.4. (M+H)⁺.

Step 4—Tert-butylN-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy] ethyl]carbamate (950 mg, 1.78 mmol) in MeOH (20 mL) was addedPd(OH)₂/C (500 mg, 10 wt %), Pd/C (500 mg, 10 wt %) and NH₃ H₂O (1.92 g,20.7 mmol, 38 wt %) under nitrogen atmosphere. The suspension wasdegassed under vacuum and purged with hydrogen gas three times. Thereaction mixture was stirred under hydrogen atmosphere (15 psi pressure)at rt for 55 h. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound (550 mg, 88% yield) asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ=5.51 (s, 1H), 4.32-4.15 (m,1H), 3.67-3.57 (m, 8H), 3.54 (t, J=5.2 Hz, 2H), 3.36-3.28 (m, 2H),3.07-2.96 (m, 1H), 2.95-2.85 (m, 1H), 1.45 (s, 9H), 1.23 (dd, J=1.6, 10Hz, 6H); LC-MS (ESI)⁺ m/z 353.2. (M+H)⁺.

Tert-ButylN-[2-[2-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxyethyl]ethyl]carbamate(Intermediate AS)

Step 1—Tert-ButylN-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of 4-(dibenzylamino)-3-fluoro-butan-2-ol (968 mg, 3.37mmol, Intermediate AL) in DMF (20 mL) was added NaH (404 mg, 10.1 mmol,60% dispersion in mineral oil) and the reaction mixture was stirred atrt for 30 min. Then2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (2.10 g, 5.05 mmol, synthesized via Steps 1-2 ofIntermediate AK) was added into the mixture and the reaction was stirredat rt for 12 h. On completion, the reaction mixture was quenched byaddition H₂O (20 mL) and extracted with ethyl acetate (2×30 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (0.1% NH₃ H₂O condition) to give the title compound (640 mg,25% yield) as a yellow oil. LC-MS (ESI⁺) m/z 607.3 (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (840 mg, 1.38 mmol) in MeOH (20 mL)and NH₃ H₂O (1 mL) was added Pd(OH)₂/C (300 mg, 10 wt %) and Pd/C (300mg, 10 wt %). The reaction mixture was stirred under hydrogen atmosphere(50 psi pressure) at rt for 12 h. On completion, the mixture wasfiltered, and the filtrate was concentrated in vacuo to give the titlecompound (540 mg, 91% yield) as a colorless oil. LC-MS (ESI⁺) m/z 427.2(M+H)⁺.

Tert-ButylN-[3-[3-(3-amino-2-fluoro-1,1-dimethyl-propoxy)propoxy]propyl]carbamate(Intermediate AT)

Step 1—2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetic Acid

To a solution of ethyl2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetate (5.00 g, 12.9mmol, synthesized via Steps 1-2 of Intermediate AN) in THF (50.0 mL) andH₂O (30.0 mL) was added LiOH (1.24 g, 51.6 mmol) and the reactionmixture was stirred at rt for 6 h. On completion, the mixture wasconcentrated and acidified with 5 N HCl (1 mL) until pH=5 and was thenconcentrated in vacuo again. The residue was purified by reverse phasechromatography (0.1% FA) to give the title compound (3.50 g, 64% yield)as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.50-7.31 (m, 10H),4.64-4.44 (m, 1H), 4.06-3.96 (m, 6H), 3.07-2.77 (m, 2H), 1.10 (s, 3H),1.07 (s, 3H)

Step 2—2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetylChloride

To a solution of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetic acid (2.00 g,5.56 mmol) in DCM (40.0 mL) was added DMF (4.07 mg, 55.6 umol, 4.28 uL)and (COCl)₂ (2.12 g, 16.6 mmol, 1.46 mL) at 0° C., then reaction mixturewas allowed to warm to rt and stirred for 3 h. On completion, themixture was concentrated in vacuo to give the title compound (2.00 g,98% yield) as a light yellow oil. LC-MS (ESI⁺) m/z 388.2 (M+H)⁺ (+OEtfrom quench with ethanol).

Step3—1-diazo-3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propan-2-one

To a solution of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetyl chloride (3.40g, 9.00 mmol) in THF (20.0 mL) and ACN (20.0 mL) was dropwise addedTMSCHN₂ (2 M, 9.00 mL) at 0° C. Then the reaction mixture was allowed towarm to rt and stirred for 19 h. On completion, the mixture wasconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (PE:EA=5:1) to give the title compound (2.30 g,65% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.46-7.21 (m,10H), 5.08 (s, 1H), 4.61-4.45 (m, 1H), 3.92-3.80 (m, 4H), 3.60-3.50 (m,2H), 3.00-2.62 (m, 2H), 1.13 (s, 3H), 1.10 (s, 3H)

Step 4—Methyl3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propanoate

To a solution of1-diazo-3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propan-2-one(2.00 g, 5.22 mmol) in MeOH (30 mL) was added Ag₂O (120 mg, 521 umol)and the reaction mixture was stirred at 50° C. for 16 h. On completion,the mixture was filtered and concentrated in vacuo to give a residue.The residue was purified by silica gel chromatography (PE:EA=5:1) togive the title compound (1.10 g, 48% yield) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 7.43-7.20 (m, 10H), 4.61-4.42 (m, 1H), 3.81-3.73 (m,2H), 3.66 (s, 3H), 3.63-3.49 (m, 4H), 2.94-2.63 (m, 2H), 2.40-2.36 (m,2H), 1.11 (s, 3H), 1.08 (s, 3H)

Step 5—3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propan-1-ol

To a solution of methyl3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propanoate (900 mg,2.32 mmol) in THF (15.0 mL) was added LiAlH₄ (116 mg, 3.02 mmol, 98%purity) at 0° C. under nitrogen atmosphere. The reaction mixture wasallowed to warm to rt and stirred for 1 hr. On completion, the mixturewas quenched with water (1 mL) and 15% NaOH (1.5 mL) at 0° C. Themixture was then filtered, dried over Na₂SO₄, filtered again andconcentrated in vacuo to give the title compound (800 mg, 90% yield) asa colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.21 (m, 10H), 4.64-4.45(m, 1H), 3.82-3.77 (m, 2H), 3.66-3.56 (m, 4H), 3.55-3.41 (m, 2H),2.96-2.63 (m, 2H), 2.28 (s, 1H), 1.68-1.62 (m, 2H), 1.11 (s, 3H), 1.09(s, 3H).

Step6—3-[3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propoxy]propanenitrile

To a mixture of3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propan-1-ol (560 mg,1.56 mmol) and prop-2-enenitrile (1.60 g, 30.1 mmol, 2.00 mL) was addedNaOMe (841 ug, 15.5 umol), and the reaction mixture was stirred at rtfor 50 h. On completion, the mixture was concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatography(PE:EA=5:1) to give the title compound (550 mg, 83% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.20 (m, 10H), 4.64-4.43(m, 1H), 3.80-3.77 (m, 2H), 3.66-3.52 (m, 4H), 3.44-3.28 (m, 4H),3.00-2.62 (m, 2H), 2.56-2.53 (m, 2H), 1.70-1.60 (m, 2H), 1.11 (s, 3H),1.07 (s, 3H).

Step7—3-[3-(3-aminopropoxy)propoxy]-N,N-dibenzyl-2-fluoro-3-methyl-butan-1

A solution of BH₃-Me₂S (10 M, 145 uL) in THF (20.0 mL) was added to asolution of3-[3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propoxy]propanenitrile(300 mg, 727 umol) in THF (5.00 mL) at 0° C. and stirred for 30 min.Then the reaction mixture was heated to 70° C. and stirred for 16 h. Oncompletion, the mixture was quenched with MeOH (3 mL) and concentratedin vacuo to give the title compound (300 mg, 65% yield) as yellow oil.LC-MS (ESI⁺) m/z 417.4 (M+H)⁺.

Step 8—Tert-ButylN-[3-[3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propoxy]propyl]carbamate

To a solution of3-[3-(3-aminopropoxy)propoxy]-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine(300 mg, 720 umol) in DCM (5.00 mL) was added (Boc)₂O (314 mg, 1.44mmol, 330 uL) and the reaction mixture was stirred at rt for 2 h. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% NH₃ H2O) to give thetitle compound (180 mg, 45% yield) as a yellow solid. LCMS (M+1)⁺:517.3.

Step 9—Tert-ButylN-[3-[3-(3-amino-2-fluoro-1,1-dimethyl-propoxy)propoxy]propyl]carbamate

To a solution of tert-butylN-[3-[3-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]propoxy]propyl]carbamate (180 mg, 348 umol) and NH₃ H2O (151 mg, 1.30 mmol, 166uL, 30 wt %) in MeOH (5.00 mL) was added Pd/C (90.0 mg, 348 umol, 10 wt%) and Pd(OH)₂/C (90.0 mg, 348 umol, 10 wt %) under nitrogen. Thesuspension was degassed under vacuum and purged with hydrogen gasseveral times. The reaction mixture was stirred under hydrogenatmosphere (50 psi pressure) at rt for 16 h. On completion, the mixturewas filtered and the filtrate concentrated in vacuo to give the titlecompound (70.0 mg, 59% yield) as a yellow oil. LC-MS (ESI⁺) m/z 337.2(M+H)⁺

Tert-ButylN-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethyl]carbamate(Intermediate AU)

Step 1—Ethyl2-[2-[3-(Dibenzylamino)-2-Fluoro-1,1-Dimethyl-Propoxy]Ethoxy]acetate

To a solution of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol (4.00 g, 11.6mmol, Intermediate AN) and Rh(OAc)₂ (128 mg, 579 umol) in DCM (80 mL)was added a solution of ethyl 2-diazoacetate (3.96 g, 34.7 mmol) in DCM(40 mL) dropwise at rt. The reaction mixture was stirred at rt for 20 h.On completion, the reaction mixture was diluted with H₂O (60 mL) andextracted with DCM (2×50 mL). The organic layer was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(4.63 g, 93% yield) as a yellow oil. LC-MS (ESI⁺) m/z 432.2 (M+H)⁺.

Step2—2-[2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethanol

To a mixture of LiAlH₄ (611 mg, 16.1 mmol) in THF (20 mL) was added asolution of ethyl2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]acetate(4.63 g, 10.7 mmol) in THF (40 mL) dropwise at 0° C. The reactionmixture was stirred at 0° C. for 2 h. On completion, the reactionmixture was quenched with H₂O (0.55 mL) at 0° C. Then 15% NaOH solution(1.5 mL) was added to the reaction mixture. The mixture was filtered andthe filtrate was concentrated in vacuo to give the title compound (3.53g, 84% yield) as a yellow oil.

Step3—2-[2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethylMethanesulfonate

To a solution of2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethanol(3.53 g, 9.06 mmol) and TEA (2.29 g, 22.7 mmol) in DCM (35 mL) was addedMsCl (1.56 g, 13.6 mmol) dropwise at 0° C. The reaction mixture wasstirred at rt for 1 hour. On completion, the mixture was quenched withH₂O (30 mL) and extracted with DCM (2×30 mL). The organic layer waswashed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (4.50 g, 100% yield) asa yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.44-7.24 (m, 10H), 4.63-4.46(m, 1H), 4.35-4.30 (m, 2H), 3.81-3.75 (m, 2H), 3.68-3.64 (m, 2H),3.63-3.59 (m, 2H), 3.54-3.39 (m, 4H), 3.04 (s, 3H), 2.96-2.67 (m, 2H),1.11 (s, 6H).

Step4—2-[2-[2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]isoindoline-1,3-dione

To a solution of2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethylmethane sulfonate (4.50 g, 9.62 mmol) in DMF (45 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (2.67 g, 14.4 mmol). The reactionmixture was stirred at 80° C. for 3 h. On completion, the mixture wasdiluted with H₂O (30 mL) and extracted with EtOAc (3×40 mL). The organiclayer was washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (5.90 g, 96% yield) asa yellowish oil. LC-MS (ESI⁺) m/z 519.3 (M+H)⁺.

Step5—3-[2-(2-Aminoethoxy)ethoxy]-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine

To a solution of2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]isoindoline-1,3-dione(4.99 g, 9.62 mmol) in EtOH (60 mL) was added NH₂NH₂ H2O (2.41 g, 48.1mmol). The reaction mixture was stirred at 80° C. for 15 hours. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to remove solvent. The residue was diluted withDCM (30 mL), filtered and the filtrate was concentrated in vacuo to givethe title compound (3.74 g, 100% yield) as a yellow oil. LC-MS (ESI⁺)m/z 389.2 (M+H)⁺.

Step 6—Tert-ButylN-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]carbamate

To a solution of3-[2-(2-aminoethoxy)ethoxy]-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine(3.74 g, 9.63 mmol) in DCM (40 mL) was added (Boc)₂O (4.20 g, 19.3mmol). The reaction mixture was stirred at rt for 3 hours. Oncompletion, the reaction mixture was concentrated in vacuo to removesolvent. The residue was purified by reverse phase chromatography (0.1%NH₃ H₂O) to give the title compound (3.10 g, 66% yield) as a yellow oil.LC-MS (ESI⁺) m/z 489.1 (M+H)⁺.

Step 7—Tert-ButylN-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]carbamate (3.10 g, 6.34 mmol) in MeOH (30 mL) was added Pd/C (1.5 g, 10wt %), Pd(OH)₂/C (1.5 g, 10 wt %) and NH₃ H2O (910 mg, 6.49 mmol, 25 wt%). The reaction mixture was stirred at rt for 17 h under hydrogenatmosphere (15 psi pressure). On completion, the mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(1.82 g, 93% yield) as a yellow oil. LC-MS (ESI⁺) m/z 309.1 (M+H)⁺.

Tert-Butyl N-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethyl]carbamate(Intermediate AV)

Step1—2-[2-[2-[3-(Dibenzylamino)-2-fluoro-propoxy]ethoxy]ethyl]isoindoline-1,3-dione

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (1.00 g, 3.66mmol, Intermediate AH) in DMF (15.0 mL) was added NaH (439 mg, 10.9mmol, 60% dispersion in mineral oil) under 0° C. and the mixture wasstirred at 0° C. for 30 minutes. Then2-[2-(2-bromoethoxy)ethyl]isoindoline-1,3-dione (1.64 g, 5.49 mmol,Intermediate AQ) was added and the mixture was allowed to warm to rt andstirred 4 h. On completion, the mixture was quenched with H₂O (1 mL) andconcentrated in vacuo to give the title compound (1.79 g, 80% yield) asyellow solid. LC-MS (ESI⁺) m/z 491.3 (M+H)⁺.

Step 2—3-[2-(2-Aminoethoxy)ethoxy]-N,N-dibenzyl-2-fluoro-propan-1-amine

To a solution of2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethyl]isoindoline-1,3-dione(2.68 g, 5.46 mmol) in EtOH (30.0 mL) was added N₂H4H₂O (5.58 g, 109mmol, 5.42 mL, 98% purity). The reaction mixture was stirred at 80° C.for 40 hours. On completion, the mixture was filtered, and the filtratewas concentrated in vacuo. The solid was diluted with DCM (50 mL) andstirred for 15 minutes, filtered, and the organic layer was concentratedin vacuo to give the title compound (1.97 g, 80% yield) as a yellow oil.LC-MS (ESI⁺) m/z 361.2 (M+H)⁺.

Step 3—Tert-ButylN-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethyl]carbamate

To a solution of3-[2-(2-aminoethoxy)ethoxy]-N,N-dibenzyl-2-fluoro-propan-1-amine (1.97g, 5.47 mmol) in DCM (20.0 mL) was added (Boc)₂O (2.39 g, 10.9 mmol,2.51 mL) and the reaction mixture was stirred at rt for 16 hours. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% NH₃ H2O) to give thetitle compound (930 mg, 36% yield) as a yellow oil. LC-MS (ESI⁺) m/z461.2 (M+H)⁺.

Step 4—Tert-ButylN-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethyl]carbamate (930mg, 2.02 mmol) in MeOH (10.0 mL) and NH₃·H₂O (200 uL) was added Pd/C(500 mg, 10 wt %) and Pd(OH)₂/C (500 mg, 10 wt %) under nitrogenatmosphere. The suspension was degassed in vacuo and purged withhydrogen gas several times. The mixture was stirred under hydrogenatmosphere (50 psi pressure) at rt for 16 hours. On completion, themixture was filtered and concentrated in vacuo to give the titlecompound (560 mg, 98% yield) as a yellow oil. LC-MS (ESI⁺) m/z 281.1(M+H)⁺.

Tert-Butyl N-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethyl]carbamate(Intermediate AW)

Step 1—2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethylmethanesulfonate

To a mixture of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol (1.50 g, 4.34mmol, Intermediate AN) and Et₃N (1.32 g, 13.0 mmol, 1.81 mL) in DCM (10mL) was added MsCl (746 mg, 6.51 mmol). The mixture was stirred at rtfor 2 hours. On completion, the mixture was quenched with water (15 mL)and extracted with DCM (2×20 mL). The organic layer was washed withbrine (10 mL), dried over anhydrous Na₂SO₄, then filtered andconcentrated in vacuo to give the title compound (1.90 g, 98% yield) asa yellow oil. LC-MS (ESI⁺) m/z 424.2 (M+H)⁺.

Step2—2-[2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]isoindoline-1,3

To a solution of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethylmethanesulfonate (1.70 g, 4.01 mmol) in DMF (20 mL) was added(1,3-dioxoisoindolin-2-yl) potassium (817 mg, 4.42 mmol). The mixturewas heated at 60° C. for 16 hours. On completion, the mixture wasdiluted with water (10 mL) and extracted with EtOAc (2×50 mL). Theorganic layer was washed with brine (20 mL), dried over anhydrousNa₂SO₄, then filtered and concentrated in vacuo to give the titlecompound (1.90 g, 99% yield) as a yellow oil. LC-MS (ESI⁺) m/z 475.2(M+H)⁺.

Step 3—3-(2-Aminoethoxy)-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine

To a solution of2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]isoindoline-1,3-dione(1.90 g, 4.00 mmol) in EtOH (20 mL) was added NH₂NH₂ H2O (2.05 g, 40.0mmol, 1.99 mL, 98% purity). The reaction mixture was stirred at 80° C.for 16 hours. On completion, the mixture was filtered and the filtratewas concentrated in vacuo to give the title compound (2.50 g, crude) asa white solid. LC-MS (ESI⁺) m/z 345.2 (M+H)⁺.

Step 4—Tert-ButylN-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]

To a solution of3-(2-aminoethoxy)-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine (1.00 g,2.90 mmol) in MeOH (10 mL) was added (Boc)₂O (1.27 g, 5.81 mmol). Themixture was stirred at rt for 2 hours. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (1.29 g, 90% yield). ¹H NMR(400 MHz, CDCl₃) δ 7.44-7.22 (m, 10H), 4.66-4.41 (m, 2H), 3.82 (d,J=13.6 Hz, 2H), 3.60 (d, J=13.6 Hz, 2H), 3.41-3.24 (m, 2H), 3.18-3.00(m, 2H), 2.99-2.81 (m, 1H), 2.77-2.61 (m, 1H), 1.47 (s, 9H), 1.13-1.06(m, 6H); LC-MS (ESI⁺) m/z 445.3 (M+H)⁺.

Step 5—Tert-ButylN-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethyl]carbamate

To a solution of tert-butylN-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]carbamate(1.3 g, 2.9 mmol) in MeOH (15 mL) was added Pd/C (0.5 g, 10 wt %),Pd(OH)₂/C (0.5 g, 10 wt %) and NH₃ H2O (100 uL, 30 wt %, catalyticamount). The mixture was degassed and purged with hydrogen gas threetimes. The mixture was stirred at rt for 24 hours under hydrogen gas (50psi pressure). On completion, the mixture was filtered and concentratedin vacuo to give the title compound (700 mg, 90% yield) as a colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 4.93 (s, 1H), 3.57-3.43 (m, 2H),3.38-3.19 (m, 2H), 3.13-2.91 (m, 2H), 2.38-2.30 (m, 2H), 1.46 (s, 9H),1.22 (dd, J=1.2, 10.6 Hz, 6H); LC-MS (ESI⁺) m/z 265.1 (M+H)⁺.

Tert-Butyl N-[2-(3-amino-2-fluoro-propoxy)ethyl]carbamate (IntermediateAX)

Step 1—Ethyl 2-[3-(dibenzylamino)-2-fluoro-propoxy]acetate

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (5.00 g, 18.2mmol, Intermediate AH) in DCM (100 mL) was added [Rh(OAc)₂]₂ (80.8 mg,365 umol) in DCM (50.0 mL) then and ethyl 2-diazoacetate (6.26 g, 54.8mmol, 5.74 mL) was added dropwise. The reaction mixture was stirred atrt for 60 h. On completion, the mixture was concentrated in vacuo. Themixture was purified by reverse phase column (0.1% NH₃ H₂O) to give thetitle compound (7.23 g, 78% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.25 (m, 10H), 4.92-4.71 (m, 1H), 4.28-4.18 (m, 2H),4.13-4.08 (m, 2H), 3.79-3.53 (m, 6H), 2.82-2.71 (m, 2H), 1.30 (t, J=7.2Hz, 3H).

Step 2—2-[3-(Dibenzylamino)-2-fluoro-propoxy]ethanol

To a solution of LiAlH₄ (1.15 g, 30.1 mmol) in THF (70.0 mL) was added asolution of ethyl 2-[3-(dibenzylamino)-2-fluoro-propoxy] acetate (7.23g, 20.1 mmol) dissolved in THF (30.0 mL) dropwise at 0° C. The reactionmixture was stirred at 0° C. for 2 h. On completion, the mixture wasquenched with water (3 mL), then 15% NaOH (3 mL) was added until noprecipitate formed. The reaction mixture was then filtered and thefiltrate was concentrated in vacuo to give the title compound (5.88 g,92% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.26 (m,10H), 4.86-4.64 (m, 1H), 3.71-3.61 (m, 8H), 3.58-3.51 (m, 3H), 2.80-2.70(m, 2H).

Step 3—2-[3-(Dibenzylamino)-2-fluoro-propoxy]ethyl Methanesulfonate

To a solution of 2-[3-(dibenzylamino)-2-fluoro-propoxy]ethanol (2.00 g,6.30 mmol) and TEA (1.28 g, 12.6 mmol, 1.75 mL) in DCM (20.0 mL) wasadded MsCl (866 mg, 7.56 mmol, 585 uL) at 0° C. The reaction mixture wasthen allowed to warm to rt and stirred for 1 hr. On completion, themixture was diluted with DCM (30 mL), then washed with H₂O (3×30 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (2.27 g, 90% yield) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.25 (m, 10H), 4.83-4.63(m, 1H), 4.33-4.28 (m, 2H), 3.69-3.66 (m, 6H), 3.64-3.55 (m, 2H), 2.99(s, 3H), 2.81-2.69 (m, 2H)

Step4—2-[2-[3-(Dibenzylamino)-2-fluoro-propoxy]ethyl]isoindoline-1,3-dione

To a solution of 2-[3-(dibenzylamino)-2-fluoro-propoxy]ethylmethanesulfonate (2.27 g, 5.74 mmol) in DMF (20.0 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (1.59 g, 8.61 mmol) and the reactionmixture was stirred at 80° C. for 3 h. On completion, the mixture wasdiluted with water (50 mL) then extracted with EtOAc (3×30 mL). Theorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (2.56 g, 80% yield) asa yellow oil. LC-MS (ESI⁺) m/z 447.2 (M+H)⁺.

Step 5—3-(2-Aminoethoxy)-N,N-dibenzyl-2-fluoro-propan-1-amine

To a solution of2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]isoindoline-1,3-dione(2.56 g, 5.73 mmol) in EtOH (25.0 mL) was added N₂H₄ H2O (1.46 g, 28.6mmol, 1.42 mL, 98% purity) and the reaction mixture was stirred at 80°C. for 16 h. On completion, the mixture was filtered, and the filtratewas concentrated in vacuo. The resulting residue was diluted with DCM(50 mL), stirred for 15 min, filtered, and the filtrate was concentratedin vacuo to give the title compound (1.50 g, 82% yield) as a yellow oil.LC-MS (ESI⁺) m/z 317.1 (M+H)⁺.

Step 6—Tert-butylN-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]carbamate

To a solution of 3-(2-aminoethoxy)-N,N-dibenzyl-2-fluoro-propan-1-amine(1.50 g, 4.74 mmol) in DCM (15.0 mL) was added (Boc)₂O (1.55 g, 7.11mmol, 1.63 mL) and the reaction mixture was stirred at rt for 16 h. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% NH₃ H2O) to give thetitle compound (1.37 g, 67% yield) as a yellow oil. LC-MS (ESI⁺) m/z417.2 (M+H)⁺.

Step 7—Tert-Butyl N-[2-(3-amino-2-fluoro-propoxy)ethyl]carbamate

To a solution of tert-butylN-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]carbamate (1.30 g, 3.12mmol) in a solvent mixed solution of MeOH (15.0 mL) and NH₃ H2O (300 uL)was added Pd/C (600 mg, 10 wt %) and Pd(OH)₂/C (600 mg, 10 wt %) undernitrogen atmosphere. The suspension was degassed under vacuum and purgedwith hydrogen gas several times. The mixture was stirred under hydrogenatmosphere (50 psi pressure) at rt for 16 h. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo to give thetitle compound (730 mg, 99% yield) as a yellow oil. LC-MS (ESI⁺) m/z237.0 (M+H)⁺.

Tert-Butyl N-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethyl]carbamate(Intermediate AY)

Step 1—Ethyl 2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]acetate

To a mixture of 4-(dibenzylamino)-3-fluoro-butan-2-ol (1.00 g, 3.48mmol, Intermediate AL) and [Rh(OAc)₂]₂ (15.3 mg, 69.6 umol) in DCM (20mL) was added a solution of ethyl 2-diazoacetate (1.19 g, 10.4 mmol) inDCM (10 mL) dropwise. The reaction mixture was stirred at rt for 20 h.On completion, the reaction mixture was poured into 30 mL of water andextracted with DCM (3×30 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by reverse phase chromatography (0.1% NH₃ H2O) togive the title compound (890 mg, 67% yield) as a light yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 7.45-7.22 (m, 10H), 4.83-4.50 (m, 1H), 4.25-4.00(m, 4H), 3.81-3.57 (m, 5H), 2.99-2.75 (m, 2H), 1.31-1.26 (m, 3H),1.12-1.02 (m, 3H); LC-MS (ESI⁺) m/z 374.1 (M+H)⁺.

Step 2—2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethanol

To a mixture of ethyl2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]acetate (890 mg, 2.38mmol) in THF (3 mL) was added LiAlH₄ (138 mg, 3.57 mmol, 98% purity) at0° C. The reaction mixture was then allowed to warm to rt and stirred 30min. On completion, the reaction mixture was quenched with water (0.5mL) and NaOH solution (15%, 0.5 mL) at 0° C. Then the mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (730 mg, 95% yield) as a light yellow oil. LC-MS (ESI⁺) m/z332.1 (M+H)⁺.

Step 3—2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethylMethanesulfonate

To a mixture of 2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethanol(730 mg, 2.20 mmol) and TEA (668 mg, 6.61 mmol) in DCM (10 mL) was addedMsCl (378 mg, 3.30 mmol) at 0° C. The reaction mixture was allowed towarm to rt and stirred for 2 h. On completion, the reaction mixture wasdiluted with water (20 mL) and extracted with DCM (3×50 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedin vacuo to give the title compound (900 mg, 100% yield) as a lightyellow oil. LC-MS (ESI⁺) m/z 410.1 (M+H)⁺.

Step4—2-[2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethyl]isoindoline-1,3-dione

To a mixture of 2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethylmethanesulfonate (900 mg, 2.20 mmol) in DMF (10 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (610 mg, 3.30 mmol). The reactionmixture was stirred at 100° C. for 3 h. On completion, the reactionmixture was concentrated in vacuo to give the title compound (1.00 g,95% yield) as a light yellow solid. LC-MS (ESI⁺) m/z 461.2 (M+H)⁺.

Step 5—3-(2-Aminoethoxy)-N,N-dibenzyl-2-fluoro-butan-1-amine

To a mixture of2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethyl]isoindoline-1,3-dione(1.00 g, 2.17 mmol) in EtOH (15 mL) was added NH₂NH₂ H2O (869 mg, 17.3mmol). The reaction mixture was stirred at 80° C. for 20 h. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was poured into 30 mL of DCM, filtered and concentrated invacuo to give the title compound (800 mg, 73% purity, 75% yield) as alight yellow solid. LC-MS (ESI⁺) m/z 333.1 (M+H)⁺.

Step 6—Tert-ButylN-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethyl]carbamate

To a mixture of 3-(2-aminoethoxy)-N,N-dibenzyl-2-fluoro-butan-1-amine(800 mg, 2.42 mmol) in DCM (10 mL) was added (Boc)₂O (1.06 g, 4.84mmol). The reaction mixture was stirred at rt for 2 h. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby reverse phase chromatography (0.1% NH₃ H2O) to give the titlecompound (520 mg, 48% yield) as a light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.23 (m, 10H), 4.87-4.41 (m, 2H), 3.81-3.68 (m, 2H),3.68-3.59 (m, 2H), 3.59-3.44 (m, 2H), 3.39-3.24 (m, 1H), 3.19 (d, J=5.2Hz, 2H), 2.91-2.65 (m, 2H), 1.48-1.45 (m, 9H), 1.07-0.98 (m, 3H); LC-MS(ESI⁺) m/z 431.2 (M+H)⁺.

Step 7—Tert-ButylN-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethyl]carbamate

To a mixture of tert-butylN-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethyl]carbamate (520mg, 1.21 mmol), Pd/C (300 mg, 10 wt %) and Pd(OH)₂/C (300 mg, 10 wt %)in MeOH (10 mL) was added NH₃ H₂O (169 mg, 1.21 mmol 25% wt %) underhydrogen atmosphere (15 psi pressure). The reaction mixture was stirredat rt for 16 h. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound (280 mg, 100% yield) asa light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.09-4.78 (m, 1H),4.41-4.07 (m, 1H), 3.63-3.49 (m, 2H), 3.47-3.38 (m, 1H), 3.26-3.16 (m,2H), 2.96-2.77 (m, 2H), 1.70-1.60 (m, 2H), 1.38 (s, 9H), 1.14-1.10 (m,3H).

Tert-ButylN-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethyl]carbamate(Intermediate AZ)

Step 1—Ethyl2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]acetate

To a solution of 2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethanol(3.30 g, 9.96 mmol, synthesized via Steps 1-2 of Intermediate AY) in DCM(50 mL) was added Rh(OAc)₂ (44 mg, 199 umol), then a solution of ethyl2-diazoacetate (3.41 g, 29.9 mmol, 3.13 mL) in DCM (50 mL) was addeddropwise. The mixture was stirred at rt for 20 h. On completion, themixture was concentrated in vacuo and the residue was purified by silicagel chromatography to give the title compound (2.70 g, 58% yield) as acolorless oil. LC-MS (ESI⁺) m/z 418.1 (M+H)⁺.

Step 2—2-[2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethanol

To a solution of ethyl2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]acetate (1.00g, 2.40 mmol) in THF (30 mL) was added LiAlH₄ (136 mg, 3.59 mmol). Themixture was stirred at 0° C. for 1 hr. On completion, the mixture wasquenched by adding water (1 mL), 15% NaOH (3 mL) then more water (1 mL).A large quantity of white precipitate was formed, the mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (880 mg, 93% yield) as a colorless oil. LC-MS (ESI⁺) m/z 376.2(M+H)⁺.

Step 3—2-[2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethylMethanesulfonate

To a solution of2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethanol (2.40g, 6.39 mmol) in DCM (25 mL) was added Et₃N (1.94 g, 19.2 mmol, 2.67 mL)and MsCl (1.10 g, 9.59 mmol, 742 uL). The mixture was stirred at 0° C.for 1 hr. On completion, the reaction was quenched with water (20 mL)and extracted with DCM (2×30 mL). The combined organic layer was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound (2.90 g, 98% yield) as a yellow oil.LC-MS (ESI⁺) m/z 454.1 (M+H)⁺.

Step4—2-[2-[2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethyl]isoindoline-1,3-dione

To a solution of2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethylmethanesulfonate (2.90 g, 6.39 mmol) in DMF (30 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (1.30 g, 7.03 mmol). The mixture wasstirred at 60° C. for 10 h. On completion, the mixture was diluted withwater (50 mL) and extracted with EtOAc (2×100 mL). The combined organiclayer was washed with brine (50 mL), dried over anhydrous Na₂SO₄, thenfiltered and concentrated in vacuo to give the title compound (3.8 g) asa light yellow oil. LC-MS (ESI⁺) m/z 505.2 (M+H)⁺.

Step 5—3-[2-(2-Aminoethoxy)ethoxy]-N,N-dibenzyl-2-fluoro-butan-1-amine

To a solution of2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethyl]isoindoline-1,3-dione(3.80 g, 7.53 mmol) in EtOH (50 mL) was added NH₂NH₂ H2O (3.85 g, 75.3mmol, 3.73 mL, 98% purity). The mixture was stirred at 90° C. for 3 h.On completion, the mixture was concentrated in vacuo to give the titlecompound (3.00 g, 100%) as a white solid. LC-MS (ESI⁺) m/z 375.1 (M+H)⁺.

Step 6—Tert-butylN-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethyl]carbamate

To a solution of3-[2-(2-aminoethoxy)ethoxy]-N,N-dibenzyl-2-fluoro-butan-1-amine (3.00 g,8.01 mmol) in MeOH (30 mL) was added (Boc)₂O (3.50 g, 16.02 mmol, 3.68mL). The mixture was stirred at rt for 16 h. On completion, the mixturewas concentrated in vacuo and the residue was purified by silica gelchromatography to give the title compound (4.00 g, 100%) as a whitesolid. LC-MS (ESI⁺) m/z 475.2 (M+H)⁺.

Step 7—Tert-ButylN-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethyl]carbamate(2.00 g, 4.21 mmol) in MeOH (20 mL) was added Pd/C (400 mg, 10 wt %),Pd(OH)₂/C (400 mg, 10 wt %), NH₃ H2O (404 mg, 3.46 mmol, 30 wt %). Thesuspension was degassed and purged with hydrogen gas three times. Themixture was stirred under hydrogen atmosphere (15 psi pressure) at rtfor 36 h. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (400 mg, 32% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.36-5.13 (m, 1H), 4.54-4.29(m, 1H), 3.79-3.46 (m, 7H), 3.33 (s, 2H), 3.08-2.73 (m, 2H), 1.71 (s,2H), 1.57-1.38 (m, 9H), 1.36-1.14 (m, 3H).

Tert-ButylN-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate BA)

Step 1—Tert-ButylN-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethyl]-carbamate

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (550 mg, 2.01mmol, Intermediate AH) in N,N-dimethylformamide (16 mL) was added sodiumhydroxide (241 mg, 6.04 mmol, 60% dispersion in mineral oil). Themixture was stirred at 0° C. for 30 minutes then2-[2-[2-[2-(tert-butoxycarbonylamino) ethoxy]ethoxy]-ethoxy]ethylmethanesulfonate (747 mg, 2.01 mmol, Intermediate AO) was added. Then,the reaction mixture was allowed to warm to rt and stirred for 4.5 hoursunder nitrogen atmosphere. On completion, the reaction mixture wasquenched by addition of ice water (30 mL) and extracted with ethylacetate (3×20 mL). The organic phase was collected, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to get a residue. Theresidue was purified by reversed phase chromatography (0.1% NH₃ H2O) togive the title compound (600 mg, 54% yield) as a colorless gum. ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.23 (m, 10H), 5.08 (m, 1H), 4.89-4.70 (m, 1H),3.69-3.60 (m, 17H), 3.57-3.52 (m, 3H), 3.36-3.29 (m, 2H), 2.77 (d, J=5.4Hz, 1H), 2.72 (d, J=5.4 Hz, 1H), 1.46 (s, 9H).

Step 2—Tert-ButylN-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]-ethyl]carbamate(600 mg, 1.09 mmol) in methanol (20 mL) was added Pd/C (300 mg, 10 wt %)and Pd(OH)₂/C (300 mg, 10 wt %) under nitrogen gas atmosphere. Thesuspension was degassed under vacuum and purged with hydrogen gasseveral times. The mixture was stirred under hydrogen gas (15 psipressure) at rt for 18 h. On completion, the reaction mixture wasfiltered through a pad of celite and the filter cake was washed withmethanol (3×10 mL). The filtrate was concentrated in vacuo to give thetitle compound (310 mg, 76% yield) as a colorless oil. LC-MS (ESI⁺) m/z369.2 (M+H)⁺.

Tert-ButylN-[2-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate BB)

Step 1—Tert-ButylN-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of 4-(dibenzylamino)-3-fluoro-butan-2-ol (476 mg, 1.66mmol, Intermediate AL) in DMF (8 mL) was added NaH (199 mg, 4.97 mmol)at 0° C. for 0.5 h. Then2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (800 mg, 2.15 mmol, Intermediate AO) was added into theabove mixture. The reaction mixture allowed to warm to rt and stirredfor 17 hrs. On completion, the reaction mixture was quenched with H₂O(20 mL) and extracted with EA (3×20 mL). The organic layer was driedwith Na₂SO₄, filtered and the filtrate was concentrated in vacuo. Theresidue was purified by reverse phase chromatography (0.1% NH₃ H₂O) togive the title compound (362 mg, 29% yield) as a yellow oil. LC-MS(ESI⁺) m/z 563.1 (M+H)⁺.

Step 2—Tert-butylN-[2-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (430 mg, 764 umol) in MeOH (10 mL) wasadded Pd/C (200 mg, wt %), Pd(OH)₂/C (200 mg, wt %) and NH₃ H₂O (182 mg,30 wt %, 1.30 mmol). The suspension was degassed and purged withhydrogen gas three times. The reaction mixture was stirred at rt for 17h under hydrogen atmosphere (50 psi pressure). On completion, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give the title compound (250 mg, 86% yield) as a yellow oil. LC-MS(ESI⁺) m/z 383.1 (M+H)⁺.

Tert-ButylN-[2-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate BC)

Step 1—Tert-ButylN-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol (800 mg, 2.32mmol, Intermediate AN) in DMF (12 mL) was added NaH (277 mg, 6.95 mmol,60% oil dispersion) at 0° C. and the mixture was stirred at 0° C. for0.5 h. Then 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethylmethanesulfonate (834 mg, 2.55 mmol, synthesized via Step 1 ofIntermediate AM) was added and the mixture was allowed to warm to rt andstirred for 5 hrs. On completion, the reaction mixture was quenched withwater (20 mL) and extracted with EtOAc (3×30 mL). The combined organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by reverse phase chromatography(0.1% NH₃ H2O) to give the title compound (700 mg, 49% yield) as acolorless oil. LC-MS (ESI⁺) m/z 577.2 (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (450 mg, 780 umol) in MeOH (10 mL) wasadded Pd(OH)₂/C (150 mg, 10 wt %), Pd/C (150 mg, 10 wt %) and NH₃ H₂O(455 mg, 4.93 mmol, 38 wt %) under nitrogen atmosphere. The suspensionwas degassed under vacuum and purged with hydrogen gas three times. Themixture was stirred under hydrogen atmosphere (15 psi pressure) at rtfor 62 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound (200 mg, 64% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.24 (s, 1H), 4.33-4.10 (m,1H), 3.70-3.58 (m, 12H), 3.54 (t, J=4.8 Hz, 2H), 3.38-3.25 (m, 2H),3.05-2.88 (m, 2H), 1.60 (br. s, 2H), 1.45 (s, 9H), 1.23 (d, J=1.6 Hz,3H), 1.20 (d, J=1.2 Hz, 3H).

Tert-ButylN-[2-(2-aminoethoxy)ethyl]-N-[2-[2-[3-(benzyloxycarbonylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]carbamate(Intermediate BD)

Step 1—Tert-ButylN-[2-[2-[3-(benzyloxycarbonylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethyl]carbamate(1.1 g, 3.57 mmol, Intermediate AU) in a mixed solvent of ACN (10 mL)and H₂O (10 mL) was added NaHCO₃ (898 mg, 10.7 mmol, 416 uL) and CbzCl(730 mg, 4.28 mmol, 608 uL). The mixture was stirred at rt for 5 h. Oncompletion, the mixture was extracted with DCM (2×20 mL) and the organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was purified by silica gelchromatography (PE:EA=3:1) to give the title compound (1.50 g, 95%yield) as a colorless oil. LC-MS (ESI⁺) m/z 465.2 (M+Na)⁺.

Step 2—BenzylN-[3-[2-(2-aminoethoxy)ethoxy]-2-fluoro-3-methyl-butyl]carbamate

To a solution of tert-butylN-[2-[2-[3-(benzyloxycarbonylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]carbamate (1.5 g, 3.4 mmol) in DCM (15 mL) was addedHCl/dioxane (4 M, 3.00 mL). The mixture was stirred at rt for 1 h. Oncompletion; the reaction mixture was concentrated in vacuo to give thetitle compound (1.3 g, 93% yield, HCl salt) as a colorless oil. LC-MS(ESI⁺) m/z 343.1 (M+H)⁺.

Step 3—BenzylN-[3-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethylamino]ethoxy]ethoxy]-2-fluoro-3-methyl-butyl]carbamate

To a solution of benzylN-[3-[2-(2-aminoethoxy)ethoxy]-2-fluoro-3-methyl-butyl]carbamate (1.3 g,3.80 mmol) in ACN (10 mL) was added K₂CO₃ (1.05 g, 7.59 mmol) and2-[2-(2-bromoethoxy)ethyl]isoindoline 1,3-dione (1.08 g, 3.61 mmol,Intermediate AQ). The mixture was stirred at 60° C. for 16 h. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (2.1 g, crude, 65%yield) as yellow oil. LC-MS (ESI⁺) m/z 560.3 (M+H)⁺.

Step 4—Tert-ButylN-[2-[2-[3-(benzyloxycarbonylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]-N-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethyl]carbamate

To a solution of benzylN-[3-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethylamino]ethoxy]ethoxy]-2-fluoro-3-methylbutyl]carbamate (2.1 g, 3.8 mmol) in ACN (20mL) was added (Boc)₂O (1.23 g, 5.63 mmol, 1.29 mL) and TEA (379 mg, 3.75mmol, 522 uL). The mixture was stirred at rt for 3 h. On completion, thereaction mixture was filtered, and the filtrate was concentrated invacuo to give a residue. The residue was purified by silica gelchromatography (PE:EA=3:1) to give the title compound (700 mg, 27%yield) as a colorless oil. LC-MS (ESI⁺) m/z 682.3 (M+Na)⁺.

Step 5—Tert-butylN-[2-(2-aminoethoxy)ethyl]-N-[2-[2-[3-(benzyloxycarbonylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-(benzyloxycarbonylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethyl]-N-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethyl]carbamate(500 mg, 757 umol) in EtOH (30 mL) was added N₂H₄·H₂O (193 mg, 3.79mmol, 187 uL, 98% purity) and the reaction mixture was stirred at 80° C.for 16 h. On completion, the mixture was filtered, and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂, DCM:MeOH=10/1). to give the title compound(340 mg, 84% yield) as a yellow oil. LC-MS (ESI⁺) m/z 530.3 (M+H)⁺.

Tert-ButylN-[2-[2-[2-(4-amino-3-fluoro-butoxy)ethoxy]ethoxy]ethyl]carbamate(Intermediate BE)

Step 1—Ethyl 4-(dibenzylamino)-3-oxo-butanoate

To a mixture of N-benzyl-1-phenyl-methanamine (49.5 g, 251 mmol, 48.1mL) ethyl 4-bromo-3-oxo-butanoate (25 g, 119 mmol) in THF (200 mL) wasadded a solution of ethyl 4-bromo-3-oxo-butanoate (25 g, 119 mmol) inTHF (50 mL) dropwise. The reaction mixture was stirred at rt for 1.5 h.On completion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by reverse phase chromatography(ACN/H₂O) to give the title compound (27 g, 69% yield) as a black brownoil. LC-MS (ESI⁺) m/z 326.1 (M+H)⁺.

Step 2—Ethyl 4-(dibenzylamino)-3-hydroxy-butanoate

To a mixture of ethyl 4-(dibenzylamino)-3-oxo-butanoate (4 g, 12.2 mmol)in EtOH (50 mL) was added NaBH₄ (930 mg, 24.5 mmol) dropwise at 0° C.The reaction mixture was then allowed to warm to rt and stirred for 2 h.On completion, the reaction mixture was quenched by saturated NH₄Clsolution (5 mL) under stirring, the reaction mixture was filtered andthe filtrate was concentrated in vacuo to give a residue. The residuewas poured into H₂O (15 mL) and extracted with EtOAc (3×30 mL). Thecombined organic layer was dried over Na₂SO₄, filtered and concentratedin vacuo to give the title compound (3.4 g, 85% yield) as a yellow oil.LC-MS (ESI⁺) m/z 328.1 (M+H)⁺.

Step 3—Ethyl 3-[tert-butyl(dimethyl)silyl]oxy-4-(dibenzylamino)butanoate

To a solution of ethyl 4-(dibenzylamino)-3-hydroxy-butanoate (3.0 g, 9.2mmol) in DCM (30 mL) was added imidazole (2.5 g, 36.7 mmol) and TBDMSCl(4.14 g, 27.4 mmol, 3.37 mL) dropwise at 0° C. The mixture was thenstirred at rt for 12 h. On completion, the reaction mixture wasfiltered, and the filtrate was concentrated in vacuo to give a residue.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=5/1,) to give the title compound (3.6 g, 88% yield)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.30-7.20 (m, 10H),4.23-4.13 (m, 1H), 4.11-3.99 (m, 2H), 3.65-3.60 (m, 2H), 3.51-3.47 (m,2H), 2.78-2.76 (m, 1H), 2.47-2.43 (m, 2H), 2.22-2.18 (m, 1H), 1.21 (t,J=7.2 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 6H).

Step 4—3-[Tert-butyl(dimethyl)silyl]oxy-4-(dibenzylamino)butan-1-ol

To a solution of ethyl3-[tert-butyl(dimethyl)silyl]oxy-4-(dibenzylamino)butanoate (3.6 g, 8.2mmol) in THF (40 mL) was added LiBH₄ (532 mg, 24.4 mmol) in portions at0° C. Then the reaction mixture was stirred at rt for 12 h. Oncompletion, the reaction mixture was quenched by sat. NH₄Cl (20 mL), andthen diluted with H₂O (20 mL) and extracted with EtOAc (2×50 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (PE/EA=5/1) to give the title compound (1.8 g, 51%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 10H),3.97-3.89 (m, 1H), 3.80-3.67 (m, 3H), 3.61-3.48 (m, 4H), 2.70-2.65 (m,1H), 2.50-2.46 (m, 1H), 1.94-1.86 (m, 1H), 1.79-1.72 (m, 1H), 0.88 (s,9H), 0.05 (d, J=5.2 Hz, 6H).

Step 5—Tert-ButylN-[2-[2-[2-[4-(dibenzylamino)-3-hydroxy-butoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of3-[tert-butyl(dimethyl)silyl]oxy-4-(dibenzylamino)butan-1-ol (1.8 g,4.50 mmol) in DMF (30 mL) was added NaH (540 mg, 13.5 mmol) and themixture was stirred at rt for 30 mins. Then2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate(2.21 g, 6.76 mmol, synthesized via Step 1 of Intermediate AM) wasadded. The reaction mixture was stirred at rt for 3 h. On completion,the reaction mixture was quenched with H2O (20 mL), and then extractedwith EtOAc (2×50 mL). The combined organic phase was dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by reverse phase chromatography (0.10% NH₃ H2O condition) togive the title compound (250 mg, 11% yield) as a yellow oil. LC-MS(ESI⁺) m/z 517.2 (M+H)⁺.

Step 6—Tert-butylN-[2-[2-[2-[4-(dibenzylamino)-3-fluoro-butoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[4-(dibenzylamino)-3-hydroxy-butoxy]ethoxy]ethoxy]ethyl]carbamate (230 mg, 445 umol) in THF (8 mL) was added DAST (86.1 mg, 534umol, 70.5 uL) dropwise and the mixture was stirred at rt for 1 hr. Oncompletion, the mixture was diluted with H2O (10 mL) and extracted withethyl acetate (2×20 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(200 mg, 71% yield) as a yellow oil. LC-MS (ESI⁺) m/z 519.3 (M+H).

Step 7—Tert-ButylN-[2-[2-[2-(4-amino-3-fluoro-butoxy)ethoxy]ethoxy]ethyl]carbamate

A mixture of tert-butylN-[2-[2-[2-[4-(dibenzylamino)-3-fluoro-butoxy]ethoxy]ethoxy]ethyl]carbamate (0.28 g, 539.85 umol) in MeOH (10 mL) and NH₃ H2O (0.5 mL) wasadded Pd(OH)₂/C (100 mg, 539 umol, 10 wt %) and Pd/C (100 mg, 539 umol,10 wt %). The reaction mixture was stirred at rt for 24 h under hydrogenatmosphere (50 psi pressure). On completion, the mixture was filteredand concentrated in vacuo to give the title compound (140 mg, 68% yield)as a colorless oil. LC-MS (ESI⁺) m/z 339.0 (M+H)⁺.

Tert-ButylN-[2-(2-aminoethoxy)ethyl]-N-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]carbamate(Intermediate BF)

Step1—2-[2-[2-[2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethylamino]ethoxy]ethyl]iso-indoline-1,3-dione

To a solution of 2-[2-(2-bromoethoxy)ethyl]isoindoline-1,3-dione (1.95g, 6.53 mmol, Intermediate AQ) in acetonitrile (150 mL) was addedpotassium carbonate (3.01 g, 21.7 mmol) and3-(2-aminoethoxy)-N,N-dibenzyl-2-fluoro-3-methyl-butan-1-amine (2.50 g,7.26 mmol, synthesized via Steps 1-3 of Intermediate AW). The mixturewas stirred at 80° C. for 14 h. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (4.00 g, 51% purity, 50% yield) as a light yellow gum. LC-MS(ESI⁺) m/z 562.3 (M+H)⁺.

Step 2—Tert-ButylN-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]-N-[2-[2-(1,3-di-oxoisoindolin-2-yl)ethoxy]ethyl]carbamate

To a solution of2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethylamino]ethoxy]-ethyl]isoindoline-1,3-dione(4.00 g, 51% purity, 3.63 mmol) in acetonitrile (100 mL) was added Boc₂O(2.38 g, 10.9 mmol, 2.50 mL). The mixture was stirred at 60° C. for 1hour. On completion, the reaction mixture was concentrated in vacuo toget a residue. The residue was purified by column chromatography(petroleum ether:ethyl acetate=8:1 to 5:1) to give the title compound(2.20 g, 91% yield) as a colorless gum. ¹H NMR (400 MHz, CDCl₃) δ7.88-7.82 (m, 2H), 7.74-7.68 (m, 2H), 7.40-7.38 (m, 4H), 7.32-7.29 (m,4H), 7.26-7.19 (m, 2H), 4.57-4.40 (m, 1H), 3.92-3.87 (m, 2H), 3.78-3.59(m, 6H), 3.54-3.15 (m, 8H), 2.93-2.78 (m, 1H), 2.76-2.63 (m, 1H), 1.43(s, 9H), 1.06 (s, 3H), 1.04 (s, 3H).

Step 3—Tert-ButylN-[2-(2-aminoethoxy)ethyl]-N-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethyl]-N-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethyl]carbamate(1.00 g, 1.51 mmol) in ethanol (50 mL) was added hydrazine hydrate (1.51g, 30.2 mmol, 1.47 mL). The mixture was stirred at 80° C. for 12 h. Oncompletion, the reaction mixture was concentrated in vacuo to get aresidue. Then the residue was diluted with (petroleum ether:ethylacetate=5:1, 25 mL). The insoluble substance was filtered and thefiltrate was dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to give the title compound (780 mg, 97% yield) asa colorless gum. ¹H NMR (400 MHz, CDCl₃) δ 7.34-7.28 (m, 4H), 7.26-7.20(m, 4H), 7.18-7.11 (m, 2H), 4.50-4.34 (m, 1H), 3.68 (d, J=13.6 Hz, 2H),3.53 (d, J=13.6 Hz, 2H), 3.44-3.11 (m, 10H), 2.86-2.52 (m, 4H), 1.52(br. s, 2H), 1.37 (s, 9H), 0.99 (s, 3H), 0.98 (s, 3H).

Tert-Butyl N-[5-(3-amino-2-fluoro-propoxy)pentyl]carbamate (IntermediateBG)

Step 1—2-(5-Bromopentyl)isoindoline-1,3-dione

To a solution of 1,5-dibromopentane (55.9 g, 243 mmol, 32.9 mL) inacetone (250 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (15.0 g,81.0 mmol) in portions over 30 minutes. The mixture was then stirred atrt for 30 minutes, and then heated to 60° C. and stirred for 15 hrs. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give a residue. The residue was purified by silica gel chromatography(PE:EA=15:1 to 10:1) to give the title compound (20.0 g, 82% yield) as awhite solid. LC-MS (ESI⁺) m/z 296.0 (M+H)⁺.

Step2—2-[5-[3-(Dibenzylamino)-2-fluoro-propoxy]pentyl]isoindoline-1,3-dione

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (2.00 g, 7.32mmol, Intermediate AH) in DMF (80 mL) was added NaH (878 mg, 22.0 mmol,60% oil dispersion) and the mixture was stirred at rt for 0.5 h. Then2-(5-bromopentyl)isoindoline-1,3-dione (5.20 g, 17.6 mmol) was added andthe reaction mixture was stirred at 70° C. for a further 34.5 h. Oncompletion, the reaction mixture was quenched by adding H₂O (50 mL), andthen extracted with ethyl acetate (3×20 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by reverse phase chromatography togive the title compound (560 mg, 16% yield) as colorless oil. LC-MS(ESI⁺) m/z 489.3 (M+H)⁺.

Step 3—5-[3-(Dibenzylamino)-2-fluoro-propoxy] Pentan-1-amine

To a solution of2-[5-[3-(dibenzylamino)-2-fluoro-propoxy]pentyl]isoindoline-1,3-dione(560 mg, 1.14 mmol) in EtOH (10 mL) was added NH₂NH₂ H2O (676 mg, 13.5mmol). The reaction mixture was stirred at 80° C. for 24 h. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (380 mg, 310% purity,49% yield) as a light yellow solid. LC-MS (ESI⁺) m/z 359.1 (M+H)⁺.

Step 4—Tert-ButylN-[5-[3-(dibenzylamino)-2-fluoro-propoxy]pentyl]carbamate

To a solution of 5-[3-(dibenzylamino)-2-fluoro-propoxy] pentan-1-amine(380 mg, 1.06 mmol) in DCM (10 mL) was added (Boc)₂O (462 mg, 2.12 mmol)and the reaction mixture was stirred at rt for 3 h. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (SiO₂, petroleumether:ethyl acetate=12:1) to give the title compound (390 mg, 77% yield)as a colorless oil. LC-MS (ESI⁺) m/z 459.3 (M+H)⁺.

Step 5—Tert-Butyl N-[5-(3-amino-2-fluoro-propoxy)pentyl]carbamate

To a solution of tert-butylN-[5-[3-(dibenzylamino)-2-fluoro-propoxy]pentyl]carbamate (390 mg, 816umol) in MeOH (10 mL) was added Pd(OH)₂/C (190 mg, 10 wt %), Pd/C (190mg, 10 wt %) and NH₃ H₂O (91.0 mg, 779 umol, 30 wt %) under nitrogenatmosphere. The suspension was degassed and purged with hydrogen gasseveral times. The mixture was stirred at rt for 12 h under hydrogenatmosphere (15 psi pressure). On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (206 mg, 61% purity, 55% yield) as a light yellow oil. LC-MS(ESI⁺) m/z 279.1 (M+H)⁺.

Tert-Butyl(2-(3-amino-2-fluoropropoxy)ethyl)(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)Carbamate (Intermediate BH)

Step 1—2-(3-(Dibenzylamino)-2-fluoropropoxy)ethylmethanesulfonate

To a solution of 2-[3-(dibenzylamino)-2-fluoro-propoxy]ethanol (2.00 g,6.30 mmol, synthesized via Steps 1-2 of Intermediate AX) and TEA (1.28g, 12.6 mmol, 1.75 mL) in DCM (20 mL) was added MsCl (866 mg, 7.56 mmol,585 uL) at 0° C. Then the mixture was allowed to warm to rt and stirredfor 3 h. On completion, the reaction mixture was diluted with H₂O (50mL) and extracted with DCM (3×50 mL). The combined organic layers werewashed with saturated NH₄Cl solution (3×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(2.65 g, 90% purity, 96% yield) as a colorless oil. ¹H NMR (400 MHz,CDCl₃) δ 7.45-7.25 (m, 10H), 4.85-4.65 (m, 1H), 4.38-4.27 (m, 2H),3.70-3.59 (m, 8H), 2.99 (s, 3H), 2.80-2.70 (m, 2H).

Step2—2-(2-(3-(Dibenzylamino)-2-fluoropropoxy)ethyl)isoindoline-1,3-dione

A mixture of 2-(3-(dibenzylamino)-2-fluoropropoxy)ethylmethanesulfonate(2.65 g, 6.03 mmol, 90% purity) and potassium 1,3-dioxoisoindolin-2-ide(2.23 g, 12.1 mmol) in DMF (45 mL) was stirred at 85° C. for 12 h. Oncompletion, the reaction mixture was diluted with H₂O (50 mL) andextracted with EA (200 mL). The combined organic layer was washed withbrine (3×150 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (3.00 g, 90% yield) as a yellow oil.LC-MS (ESI)⁺ m/z 447.3. (M+H)⁺.

Step 3—3-(2-Aminoethoxy)-N,N-dibenzyl-2-fluoropropan-1-amine

To a solution of2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]isoindoline-1,3-dione(3.00 g, 1.34 mmol) in EtOH (150 mL) was added N₂H₄ H₂O (5 mL, 98%purity) at rt. The mixture was stirred at 85° C. for 12 h. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was triturated with DCM (100 mL) and whiteprecipitate was filtered off. The filtrate was concentrated in vacuo togive the title compound (1.93 g, 85% purity, 86% yield) as a colorlessoil. LC-MS (ESI)⁺ m/z 317.3. (M+H)⁺.

Step4—2-(2-Benzyl-4-fluoro-1-phenyl-6,12-dioxa-2,9-diazatetradecan-14-yl)isoindoline-1,3-dione

To a mixture of 3-(2-aminoethoxy)-N,N-dibenzyl-2-fluoro-propan-1-amine(1.93 g, 5.19 mmol, 85% purity), K₂CO₃ (2.17 g, 15.6 mmol) and KI (86.2mg, 519 umol) in MeCN (50 mL) was added dropwise a solution of2-[2-(2-bromoethoxy)ethyl]isoindoline-1,3-dione (1.39 g, 4.67 mmol, 0.9eq, Intermediate AQ) in MeCN (10 mL) at rt. The reaction mixture thenheated to 80° C. and stirred for 12 h. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (3.33 g, 45% purity, 54% yield) as a colorless oil. LC-MS(ESI)⁺ m/z 534.3. (M+H)⁺.

Step 5—Tert-Butyl(2-(3-(dibenzylamino)-2-fluoropropoxy)ethyl)(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)carbamate

A mixture of2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethylamino]ethoxy]ethyl]isoindoline-1,3-dione(3.22 g, 45% purity, 2.72 mmol) and Boc₂O (1.19 g, 1.25 mL) in MeOH (30mL) was stirred at 60° C. for 6 h. On completion, the reaction mixturewas concentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether:Ethyl acetate=1:0 to 5:1)to give the title compound (1.40 g, 79% purity, 65% yield) as acolorless oil. LC-MS (ESI)⁺ m/z 634.4. (M+H)⁺.

Step 6—Tert-Butyl(2-(3-amino-2-fluoropropoxy)ethyl)(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)carbamate

A mixture of tert-butylN-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]-N-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethyl]carbamate(400 mg, 79% purity), Pd/C (200 mg, 10 wt %) and Pd(OH)₂/C (200 mg, 10wt %) in MeOH (15 mL) was purged with hydrogen gas several times. Thereaction mixture was stirred under hydrogen atmosphere (50 psi pressure)at 45° C. for 6 hours. On completion, the reaction mixture was filteredand concentrated in vacuo to give the title compound (273 mg, 71.6%purity) as a colorless oil. LC-MS (ESI)⁺ m/z 454.3. (M+H)⁺.

Ethyl 2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate(Intermediate BI)

Step 1-Ethyl 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]acetate

A solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (10.0 g, 66.6 mmol)and BF₃ Et₂O (205 mg, 665 umol) in DCM (150 mL) was cooled to 0° C. Thenethyl 2-diazoacetate (7.60 g, 66.9 mmol) was added to the mixturedropwise. After that, the mixture was stirred at rt for 12 h. Oncompletion, the reaction mixture was quenched with saturated NH₄Cl (5mL), then diluted with water (100 mL) and extracted with DCM (3×50 mL).The combined organic layers were dried over sodium sulfate, filtered,and concentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (PE:EA=1:3) to give the title compound (5.00g, 31% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.17 (q,J=7.2 Hz, 2H), 4.11 (s, 2H), 3.72-3.60 (m, 10H), 3.59-3.54 (m, 2H), 2.82(s, 2H), 1.24 (t, J=7.2 Hz, 3H).

Step 2—Ethyl 2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate

A solution of ethyl 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]acetate (900mg, 3.81 mmol) and TEA (1.16 g, 11.4 mmol) in DCM (10 mL) was cooled to0° C. Then, MsCl (523 mg, 4.57 mmol) in DCM (2 mL) was added to thereaction mixture dropwise. The mixture was stirred at rt for 1 hour. Oncompletion, the reaction mixture was quenched with water (8 mL) and thenextracted with dichloromethane (3×5 mL). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (1.10 g, 91% yield) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 4.40-4.36 (m, 2H), 4.21 (q, J=7.2 Hz, 2H), 4.13 (s, 2H),3.79-3.74 (m, 2H), 3.74-3.65 (m, 8H), 3.08 (s, 3H), 1.28 (t, J=7.2 Hz,3H).

Ethyl2-[2-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate(Intermediate BJ)

Step1—2-[2-[2-[2-[2-[3-(Dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a mixture of2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethanol (3.66 g, 10.6mmol, Intermediate AN) in DMF (40 mL) was added NaH (1.27 g, 31.8 mmol,60% dispersion in mineral oil) at 0° C. and stirred for 0.5 hour. Thenethyl 2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (4.00 g,12.7 mmol, Intermediate BI) was added and the reaction was allowed towarm to rt and stirred for 16 hours. On completion, the reaction mixturewas quenched with water (1 mL) and concentrated in vacuo to give thetitle compound (5.00 g, 88% yield) as a yellow oil. LC-MS (ESI⁺) m/z536.1 (M+H)⁺.

Step 2—Ethyl2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (5.00 g, 9.33 mmol) in EtOH (50 mL) was addedSOCl₂ (3.33 g, 28.0 mmol). The reaction mixture was stirred at 80° C.for 4 hours. On completion, the reaction mixture was concentrated invacuo. The residue was diluted with water (10 mL) and basified withNaHCO₃ until the pH=7-8, then the mixture was extracted with EA (3×20mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byreverse phase chromatography (0.1% NH₃ H₂O) to give the title compound(1.80 g, 34% yield) as a light yellow oil. LC-MS (ESI⁺) m/z 564.4(M+H)⁺.

Step 3—Ethyl2-[2-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of ethyl2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate (900 mg, 1.60 mmol) and Pd(OH)₂/C (600 mg, 10%purity) in EtOH (10 mL) was added TFA (161 mg, 1.60 mmol) under hydrogenatmosphere (15 psi pressure). The reaction mixture was stirred at rt for16 hours. On completion, the reaction mixture was concentrated in vacuoto give the title compound (610 mg, 90% yield) as a light yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 4.54-4.37 (m, 1H), 4.24 (q, J=7.6 Hz, 2H), 4.15(s, 2H), 3.80-3.50 (m, 18H), 3.31-3.01 (t, J=7.6 Hz, 3H), 1.31-1.23 (m,6H).

Ethyl 2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate(Intermediate BK)

Step 1—Ethyl 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate

A solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (10.0 g,51.5 mmol, CAS #112-60-7) and BF₃·Et₂O (159 mg, 515 umol) in DCM (150mL) was cooled to 0° C. Then ethyl 2-diazoacetate (5.87 g, 51.5 mmol)was added to the solution dropwise. After that, the mixture was stirredat rt for 12 h. On completion, the reaction mixture was quenched withsaturated NH₄Cl aqueous solution (5 mL), diluted with water (100 mL),then extracted with dichloromethane (3×50 mL). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was purified by silica gelchromatography (PE:EA=1:3) to give the title compound (2.90 g, 20%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.19 (q, J=7.2 Hz,2H), 4.12 (s, 2H), 3.73-3.63 (m, 14H), 3.61-3.56 (m, 2H), 1.26 (t, J=7.2Hz, 3H)

Step 2—Ethyl2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate

A solution of ethyl2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate (800 mg, 2.85mmol) and TEA (577 mg, 5.70 mmol) in DCM (30 mL) was cooled to 0° C.Then, a solution of MsCl (392 mg, 3.42 mmol) in DCM (4 mL) was added tothe mixture dropwise. The mixture was then allowed to warm to rt andstirred for 1 hour. On completion, the reaction mixture was quenchedwith water (25 mL), and extracted with dichloromethane (3×10 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (1.90 g, 90% yield) asa yellowish oil.

Methyl2-[2-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate(Intermediate BL)

Step1—2-[2-[2-[2-[2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a solution of 4-(dibenzylamino)-3-fluoro-butan-2-ol (600 mg, 2.09mmol, Intermediate AL) in DMF (10 mL) was added NaH (209 mg, 5.22 mmol)at 0° C. After 0.5 h, ethyl2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate (898mg, 2.51 mmol, Intermediate BK) was added to the reaction mixture. Thereaction mixture was then allowed to warm to rt and stirred for 17 h. Oncompletion, the mixture was acidified with 1N HCl solution until thepH=4-5, then concentrated in vacuo. The residue was purified by reversephase chromatography (0.1% TFA) to give the title compound (640 mg, 53%yield) as a yellow oil. LC-MS (ESI⁺) m/z 522.1 (M+H)⁺.

Step 2—Methyl2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (640 mg, 1.11 mmol) in MeOH (10 mL) was added SOCl₂(396 mg, 3.33 mmol). The reaction mixture then heated to 65° C. andstirred for 15 h. On completion, the mixture was concentrated in vacuoto remove the solvent MeOH then diluted with H₂O (20 mL). The mixturewas then basified with 1N NaOH solution until the pH=8-9, and extractedwith DCM (3×20 mL). The combined organic layer was washed with brine (30mL), dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by reverse phase chromatography (0.1% FA) to give the titlecompound (280 mg, 47% yield) as a yellow oil. LC-MS (ESI⁺) m/z 536.3(M+H)⁺.

Step 3—Methyl2-[2-[2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of methyl2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate (280 mg, 522 umol) in EtOH (4 mL) was addedPd(OH)₂/C (0.3 g, 10 wt %), Pd/C (0.3 g, 10 wt %) and TFA (59.6 mg, 523umol, 0.59 mmol). The suspension was degassed and purged with hydrogengas three times. The reaction mixture was stirred under hydrogenatmosphere (15 psi pressure) at rt for 17 h. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo to give thetitle compound (200 mg, 100% yield). ¹H NMR (400 MHz, CDCl₃) δ 4.68-4.29(m, 1H), 4.17-4.11 (m, 1H), 3.75-3.53 (m, 21H), 3.27-3.14 (m, 2H),1.21-1.18 (m, 3H).

Methyl2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]acetate(Intermediate BM)

Step 1—Ethyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate

To a mixture of 2-(2-hydroxyethoxy)ethanol (5.00 g, 47.1 mmol, 4.46 mL)and Rh₂(OAc)₄ (278 mg, 628 umol) in DCM (50 mL) was added a solution ofethyl 2-diazoacetate (3.58 g, 31.4 mmol, 3.29 mL) in DCM (35 mL)dropwise. Then, the reaction mixture was stirred at rt for 16 h. Oncompletion, the reaction mixture was quenched by adding H₂O (10 mL), andthen extracted with DCM (2×15 mL). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by silica gel column chromatography(Petroleum ether:Ethyl acetate=10:1 to 0:1) to give the title compound(1.68 g, 28% yield) as a black-brown oil. ¹H NMR (400 MHz, CDCl₃-d) δ4.22 (q, J=7.2 Hz, 2H), 4.14 (s, 2H), 3.77-3.68 (m, 6H), 3.64-3.59 (m,2H), 2.60 (s, 1H), 1.29 (t, J=7.2 Hz, 3H).

Step 2—Ethyl 2-[2-(2-methylsulfonyloxyethoxy)ethoxy]acetate

To a solution of ethyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate (800 mg,4.16 mmol) in DCM (8 mL) was added TEA (1.26 g, 12.5 mmol, 1.74 mL) andMsCl (715 mg, 6.24 mmol, 483 uL) at 0° C. The reaction mixture was thenallowed to warm to rt and stirred for 30 minutes. On completion, thereaction mixture was quenched by adding H₂O (10 mL) and then citric acid(5 mL). The mixture was then extracted with DCM (2×10 mL). The combinedorganic layers were washed with NaHCO₃ solution (20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (1.00 g, 88% yield) as a black-brown oil. ¹H NMR (400 MHz,CDCl₃) δ 4.44-4.37 (m, 2H), 4.24 (q, J=7.2 Hz, 2H), 4.17-4.12 (m, 2H),3.84-3.78 (m, 2H), 3.77-3.69 (m, 4H), 3.10 (s, 3H), 1.31 (t, J=7.2 Hz,3H).

Step3—2-[2-[2-[3-(Dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]aceticAcid

To a solution of 4-(dibenzylamino)-3-fluoro-butan-2-ol (818 mg, 2.85mmol, Intermediate AL) in DMF (10 mL) was added NaH (341 mg, 8.54 mmol,60% dispersion in mineral oil) at 0° C. and the reaction was stirred for0.5 hour. Then, ethyl 2-[2-(2-methylsulfonyloxyethoxy)ethoxy]acetate(1.00 g, 3.70 mmol) was added, and the reaction mixture was allowed towarm to rt and stirred for a further 16.5 h. On completion, the reactionmixture was adjusted to pH<7 with 10% hydrochloride acid, and thenconcentrated in vacuo to give the title compound (3.00 g, 31% purity,76% yield,) as a black-brown gum. LC-MS (ESI⁺) m/z 434.1 (M+H)⁺.

Step 4—Methyl2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]acetate

To a solution of2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]aceticacid (3.00 g, 6.92 mmol) in MeOH (30 mL) was added SOCl₂ (2.47 g, 20.8mmol, 1.51 mL). The reaction mixture then heated to 65° C. and stirredfor 15 h. On completion, the reaction mixture was concentrated in vacuo.The residue was then adjusted to pH>8 with saturated NaHCO₃ solution,and then extracted with ethyl acetate (2×20 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was purified by silica gel columnchromatography (petroleum ether:ethyl acetate=30:1 to 10:1) first, andthen purified by reverse phase column chromatography (0.10% FA) to givethe title compound (250 mg, 95% purity, 8% yield) as a brown oil. ¹H NMR(400 MHz, CDCl₃) δ 7.30-7.15 (m, 10H), 4.65-4.36 (m, 1H), 4.07 (d, J=3.2Hz, 2H), 3.69-3.43 (m, 15H), 3.43-3.35 (m, 1H), 2.77-2.62 (m, 2H),0.99-0.92 (m, 3H).

Step 5—Methyl2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]acetate

To a solution of methyl2-[2-[2-[3-(dibenzylamino)-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]acetate(250 mg, 559 umol) in MeOH (5 mL) was added Pd/C (120 mg, 10 wt %),Pd(OH)₂/C (120 mg, 10 wt %) and HCl (1 M, 2.5 mL). The reaction mixturewas stirred at rt for 15 h under hydrogen atmosphere (15 psi pressure).On completion, the reaction mixture was filtered and the filtrateconcentrated in vacuo to give the title compound (200 mg, 92% purity,100% yield) as a light yellow oil. LC-MS (ESI⁺) m/z 254.1 (M+H)⁺.

Step 6—Methyl2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl]-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-1-methyl-propoxy]ethoxy]ethoxy]acetate

To a solution of2-[2-[2-(3-amino-2-fluoro-1-methyl-propoxy)ethoxy]ethoxy]acetic acid(140 mg, 553 umol) in MeOH (3 mL) was added SOCl₂ (197 mg, 1.66 mmol,120 uL). The reaction mixture was then heated to 65° C. and stirred for3 h. On completion, the reaction mixture was concentrated in vacuo togive the title compound (120 mg, 85% purity, 69% yield) as a yellow oil.LC-MS (ESI⁺) m/z 268.1 (M+H)⁺.

Tert-Butyl N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]carbamate(Intermediate BN)

To a solution of2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (3.6 g, 9.7 mmol, Intermediate AO) in DMF (20 mL) wasadded NaN₃ (1.26 g, 19.4 mmol). The reaction mixture was then heated to80° C. and stirred for 18 h. On completion, the solvent DMF was removedin vacuo. The residue was diluted with EtOAc (50 mL), filtered and thefiltrate was removed under nitrogen gas sweep to give the title compound(3.2 g, 90% yield) as a yellow oil. LC-MS (ESI⁺) m/z 219.1 (M+H−100)⁺

2-[2-[2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylMethanesulfonate (Intermediate B1)

Step1—2-[2-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzeneSulfonate

To a solution of2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol (10.0g, 35.4 mmol, CAS #2615-15-8) in DCM (1.00 L) was added Ag₂O (9.85 g,42.5 mmol), KI (587 mg, 3.54 mmol) and 4-methylbenzenesulfonylchloride(6.75 g, 35.4 mmol). The reaction mixture was stirred under nitrogenatmosphere at rt for 24 h. On completion, the mixture was filteredthrough a pad of celite and the filtrate was concentrated in vacuo togive a residue. The residue was purified by silica column chromatography(DCM:MeOH=100: 1) to give the title compound (15.0 g, 97% yield) as ayellowish oil. ¹H NMR (400 MHz, CDCl₃) δ 7.73 (d, J=8.4 Hz, 2H), 7.27(d, J=8.4 Hz, 2H), 4.12-4.06 (m, 2H), 3.68-3.50 (m, 22H), 2.38 (s, 3H).

Step 2—2-[2-[2-[2-[2-(2-Azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol

To a solution of2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl4-methylbenzene sulfonate (15.0 g, 34.3 mmol) in DMF (75.0 mL) was addedNaN₃ (4.50 g, 69.2 mmol) and the mixture was heated to 80° C. andstirred for 12 h. On completion, the DMF solvent was removed undernitrogen gas sweep. Then the reaction mixture was diluted with water(100 mL) and extracted with DCM:MeOH (10: 1) (2×200 mL). The organiclayer was purged under nitrogen to give the title compound (10.0 g, 94%yield) as a colorless oil.

Step 3—2-[2-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol

To a solution of2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol (10.0g, 32.5 mmol) in EtOH (80.0 mL) was added Pd/C (4.00 g, 10 wt %). Thereaction mixture was stirred under hydrogen atmosphere (15 psi pressure)at rt for 12 h. On completion, the mixture was filtered and concentratedin vacuo to give the title compound (8.50 g, 92% yield) as a lightyellow oil. LC-MS (ESI)⁺ m/z 282.1. (M+H)⁺.

Step 4—BenzylN-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethanol (4.00g, 14.2 mmol) in ACN (40.0 mL) and H₂O (40.0 mL) was added NaHCO₃ (3.58g, 42.6 mmol) and CbzCl (2.91 g, 17.0 mmol), and the mixture was stirredat rt for 12 h. On completion, the mixture was extracted with DCM (2×100mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (DCM:MeOH=10:1) to give the title compound (4.00 g, 67%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.33 (m, 5H),5.56 (s, 1H), 5.11 (s, 2H), 3.73-3.42 (m, 23H).

Step 5—Tert-ButylN-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of benzylN-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (3.00 g, 7.22 mmol) in EtOAc (60.0 mL) was added Pd(OH)₂/C(100 mg, 2.41 mmol, 10 wt %) and (Boc)₂O (1.89 g, 8.66 mmol), and themixture was stirred at rt for 12 h. On completion, the mixture wasfiltered and concentrated in vacuo. The residue was purified by silicacolumn chromatography (DCM:MeOH=10:1) to give the title compound (2.00g, 72% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.19 (s,1H), 3.84-3.82 (m, 2H), 3.80-3.34 (m, 20H), 3.33 (s, 2H), 1.46 (s, 9H).

Step6—2-[2-[2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylMethanesulfonate

To a solution of tert-butylN-[2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.70 g, 4.46 mmol) in DCM (5.00 mL) was added MsCl (765 mg,6.68 mmol) and TEA (1.35 g, 13.3 mmol), and the mixture was stirred at0° C. for 1 h. On completion, the mixture was quenched with water (20mL) and extracted with DCM (3×30 mL). The combined organic layer waswashed with brine (3×30 mL). The organic layer was dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(1.8 g, 87% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.07 (s,1H), 4.44-4.38 (m, 2H), 3.81-3.76 (m, 2H), 3.71-3.62 (m, 16H), 3.56 (t,J=5.2 Hz, 2H), 3.39-3.29 (m, 2H), 3.11 (s, 3H), 1.46 (s, 9H).

Tert-ButylN-[2-[2-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate BP)

Step 1—Tert-ButylN-[2-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (0.50 g, 1.83mmol, Intermediate AH) in DMF (10.0 mL) was added NaH (219 mg, 5.49mmol, 60% dispersion in mineral oil), and the mixture was stirred at 0°C. for 1 h. Then2-[2-[2-[2-[2-[2-(tertbutoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (1.01 g, 2.20 mmol, Intermediate BO) was added to the reactionmixture and the mixture was allowed to warm to rt and stirred for 16 h.On completion, the mixture was quenched with water (50 mL) and extractedwith EA (3×50 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The mixture was purified by reversephase flash column chromatography (NH₃—H₂O, ACN 50%˜ 60%) to give thetitle compound (300 mg, 21% yield) as a colorless oil. LC-MS (ESI)⁺ m/z637.4. (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoropropoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (0.40 g, 628 umol) in MeOH (5.00mL) and NH₃·H₂O (0.2 mL) was added Pd(OH)₂/C (0.10 g, 10 wt %) and Pd/C(0.10 g, 10 wt %) under nitrogen atmosphere. The suspension was degassedand purged with hydrogen gas three times. The mixture was stirred underhydrogen atmosphere (50 psi pressure) at rt for 12 h. On completion, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give the title compound (210 mg, 73% yield) as a colorless oil. LC-MS(ESI)⁺ m/z 457.1. (M+H)⁺.

Tert-ButylN-[2-[2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate BQ)

To a solution of2-[2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylmethane sulfonate (4.45 g, 9.68 mmol, Intermediate BO) in DMF (50mL) was added NaN₃ (1.26 g, 19.37 mmol). The reaction mixture thenheated to 80° C. and stirred for 16 hours. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo to give thetitle compound (3.90 g, 99% yield) as a yellow oil. LC-MS (ESI⁺) m/z424.1 (M+18)⁺.

Tert-ButylN-[2-[2-[2-[2-[2-[4-[2-(3-amino-2-fluoro-propoxy)ethyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate BR)

Step 1—Tert-Butyl 4-(2-methylsulfonyloxyethyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate(500 mg, 2.17 mmol, CAS #77279-24-4) in DCM (10 mL) at 0° C. was addedTEA (329 mg, 3.26 mmol, 451 uL). After 5 minutes, MsCl (298 mg, 2.60mmol, 201 uL) was added, and the reaction mixture was allowed to warm tort and was stirred under nitrogen atmosphere for 3 hours. On completion,the reaction mixture was diluted with H₂O (20 mL) and extracted with DCM(2×50 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo to give the title compound (620 mg, 93% yield)as a yellowish oil.

Step 2—Tert-Butyl4-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]piperazine-1-carboxylate

To a mixture of tert-butyl4-(2-methylsulfonyloxyethyl)piperazine-1-carboxylate (620 mg, 2.01 mmol)in DMF (3.00 mL) was added NaH (110 mg, 2.74 mmol, 60% dispersion inmineral oil) at rt under nitrogen atmosphere. The mixture was stirred atrt for 30 minutes, then 3-(dibenzylamino)-2-fluoro-propan-1-ol (500 mg,1.83 mmol, Intermediate AH) was added to the mixture at rt and thereaction mixture was stirred for 48 hours. On completion, the reactionmixture was quenched with sat. NH₄Cl solution (20 mL), then diluted withH₂O (20 mL) and extracted with EA (2×50 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by reversed phase flash chromatography(NH₃ H2O) to give the title compound (160 mg, 18% yield) as a yellowoil. LC-MS (ESI⁺) m/z 486.3 (M+H)⁺.

Step 3—N,N-dibenzyl-2-fluoro-3-(2-piperazin-1-ylethoxy)propan-1-amine

To a mixture of tert-butyl4-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]piperazine-1-carboxylate(160 mg, 329 umol) in DCM (5.00 mL) and MeOH (1.00 mL) was added HCl indioxane (329 umol, 2.00 mL). The mixture was stirred at rt for 1 hour.On completion, the mixture was concentrated in vacuo to give the titlecompound (200 mg) as a yellow oil. LC-MS (ESI⁺) m/z 386.2 (M+H)⁺.

Step 4—Tert-ButylN-[2-[2-[2-[2-[2-[4-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture ofN,N-dibenzyl-2-fluoro-3-(2-piperazin-1-ylethoxy)propan-1-amine (200 mg,518 umol) and2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (259 mg, 623 umol, synthesized via Steps 1-2 ofIntermediate AK) in DMF (1.00 mL) and MeCN (3.00 mL) was added K₂CO₃(215 mg, 1.56 mmol). The mixture was then heated to 80° C. and stirredfor 12 hours. On completion, the mixture was diluted with H₂O (20 mL)and extracted with ethyl acetate (2×40 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by prep-TLC (PE:EA=1:1) to give thetitle compound (220 mg, 60% yield) as a yellow oil. LC-MS (ESI⁺) m/z705.3 (M+H)⁺.

Step 5—Tert-ButylN-[2-[2-[2-[2-[2-[4-[2-(3-amino-2-fluoro-propoxy)ethyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[2-[2-[4-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (220 mg, 312umol) in MeOH (7.00 mL) was added Pd(OH)₂ (100 mg, 71.2 umol, 10 wt %)and Pd/C (100 mg, 312 umol, 10 wt %). The suspension was degassed undervacuum and purged with hydrogen gas several times. The mixture was thenstirred at rt for 192 hours under hydrogen atmosphere (50 psi pressure).On completion, the mixture was filtered and concentrated in vacuo togive the title compound (100 mg, 61% yield) as a white oil.

Tert-Butyl(15-amino-14-fluoro-13,13-dimethyl-10-oxo-3,6,12-trioxa-9-azapentadecyl)carbamate (Intermediate BS)

Step1—N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-2-((4-(dibenzylamino)-3-fluoro-2-methylbutan-2-yl)oxy)acetamide

A solution of ethyl2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetate (337 mg, 870umol, synthesized via Steps 1-2 of Intermediate AN) and2-[2-(2-aminoethoxy)ethoxy]ethanamine (644 mg, 4.35 mmol, CAS #929-59-9)in methanol (2 mL). The reaction mixture was heated to 80° C. for 12hrs. On completion, the reaction mixture was concentrated in vacuo togive the title compound (850 mg, 40% yield) as a colorless oil. LC-MS(ESI⁺) m/z 490.3 (M+H)⁺.

Step 2—Tert-Butyl(2-benzyl-4-fluoro-5,5-dimethyl-8-oxo-1-phenyl-6,12,15-trioxa-2,9-diazaheptadecan-17-yl)carbamate

To a solution ofN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetamide(920 mg, 1.60 mmol) in DCM (5 mL) was added (Boc)₂O (5.23 g, 24.0 mmol).The reaction mixture was stirred at rt for 14 h. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byreversed phase chromatography (NH₃ H2O, 0.10%) to give the titlecompound (440 mg, 44% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ=7.42-7.37 (m, 4H), 7.35-7.33 (m, 4H), 7.28-7.23 (m, 2H), 6.80 (s, 1H),5.01 (s, 1H), 4.66-4.45 (m, 1H), 3.93-3.83 (m, 2H), 3.81-3.70 (m, 2H),3.63-3.60 (d, J=14.0 Hz, 2H), 3.60-3.44 (m, 10H), 3.32-3.31 (m, 2H),2.91-2.67 (m, 2H), 1.46 (s, 9H), 1.10 (s, 6H). LC-MS (ESI⁺) m/z 590.4(M+H)⁺.

Step 3—Tert-Butyl(15-amino-14-fluoro-13,13-dimethyl-10-oxo-3,6,12-trioxa-9-azapentadecyl)carbamate

To a solution of tert-butylN-[2-[2-[2-[[2-[3-(dibenzylamino)-2-fluoro-1,1-dimethyl-propoxy]acetyl]amino]ethoxy]ethoxy]ethyl]carbamate (440 mg, 746 umol) in MeOH (5 mL)was added Pd(OH)₂/C (200 mg, 10 wt %) and Pd/C (200 mg, 10 wt %) undernitrogen atmosphere. The suspension was degassed and purged withhydrogen gas three times. The mixture was stirred under hydrogenatmosphere (55 psi pressure) at rt for 15 h. On completion, the reactionmixture was filtered and the filtrate was concentrated in vacuo to givethe title compound (270 mg, 88% yield) as a yellow solid. LC-MS (ESI⁺)m/z 410.2 (M+H)⁺.

Tert-ButylN-[2-[2-[2-(3-amino-2-fluoro-propoxy)-1-methyl-ethoxy]ethoxy]ethyl]carbamate(Intermediate

Step1—2-[2-[2-(2-Benzyloxy-1-methyl-ethoxy)ethoxy]ethyl]isoindoline-1,3-dione

To a solution of 1-benzyloxypropan-2-ol (2.5 g, 15.0 mmol, synthesizedvia Step 1 of Intermediate BU) in DMF (40 mL) was added NaH (1.80 g,45.12 mmol, 60% dispersion in mineral oil) and the mixture was stirredat rt for 30 min. Then 2-[2-(2-Bromoethoxy)ethyl]isoindoline-1,3-dione(4.48 g, 15.0 mmol, Intermediate AQ) was added to the mixture and themixture was stirred at rt for an additional 12 h. On completion, thereaction mixture was quenched with H₂O (10 mL) and then concentrated invacuo to give the title compound (5 g) as yellow solid. LC-MS (ESI⁺) m/z384.1 (M+H)⁺.

Step 2—2-[2-(2-Benzyloxy-1-methyl-ethoxy)ethoxy]ethanamine

To a solution of2-[2-[2-(2-benzyloxy-1-methyl-ethoxy)ethoxy]ethyl]isoindoline-1,3-dione(10 g, 26.0 mmol) in EtOH (100 mL) was added N₂H₄ H2O (6.66 g, 130 mmol,6.47 mL, 98% solution), and the mixture was heated to 80° C. and stirredfor 12 h. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (6 g) as a yellow oil.LC-MS (ESI⁺) m/z 254.1 (M+H)⁺.

Step 3—Tert-ButylN-[2-[2-(2-benzyloxy-1-methyl-ethoxy)ethoxy]ethyl]carbamate

To a solution of 2-[2-(2-benzyloxy-1-methyl-ethoxy)ethoxy]ethanamine (6g, 23.6 mmol) in DCM (40 mL) was added Boc₂0 (10.3 g, 47.3 mmol, 10.8mL) and the mixture was stirred at rt for 2 h. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase chromatography (NH₃ H2O) to givethe title compound (3 g, 32% yield over steps 1-3) as a white solid.LC-MS (ESI⁺) m/z 376.2 (M+Na)⁺.

Step 4—Tert-ButylN-[2-[2-(2-hydroxy-1-methyl-ethoxy)ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-(2-benzyloxy-1-methyl-ethoxy)ethoxy]ethyl]carbamate (3 g, 8.49mmol) in MeOH (30 mL) was added Pd/C (1.5 g, 10 wt %). The mixture wasthen heated to 40° C. and stirred under hydrogen atmosphere (50 psipressure) for 18 h. On completion, the reaction mixture was filtered andthe filtrate was concentrated in vacuo to give the title compound (2 g,45% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.14 (s, 1H),3.84-3.76 (m, 1H), 3.68-3.55 (m, 7H), 3.54-3.45 (m, 1H), 3.34 (J=4.8 Hz,2H), 1.46 (s, 9H), 1.15 (d, J=6.4 Hz, 3H).

Step 5—2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]propylMethanesulfonate

To a solution of tert-butylN-[2-[2-(2-hydroxy-1-methyl-ethoxy)ethoxy]ethyl]carbamate (0.44 g, 1.67mmol) in DCM (5 mL) was added TEA (507 mg, 5.01 mmol, 697 uL) and MsCl(287 mg, 2.51 mmol, 193 uL) dropwise at 0° C. The mixture was allowed towarm to rt and stirred for 3 h. On completion, the reaction mixture wasdiluted with water (10 mL) and extracted with DCM (2×20 mL). The organicphase was dried over Na₂SO₄, filtered and the filtrate was concentratedin vacuo to give the title compound (0.56 g, 90% yield) as a yellow oil.

Step 6—Tert-ButylN-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]-1-methyl-ethoxy]ethoxy]ethyl]carbamate

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (298 mg, 1.09mmol, Intermediate AH) in DMF (8 mL) was added NaH (131 mg, 3.28 mmol,60% dispersion in mineral oil) and the mixture was stirred at rt for 30min. Then 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]propylmethanesulfonate (0.56 g, 1.64 mmol) was added to the mixture and themixture was stirred at rt for an additional 12 h. On completion, thereaction mixture was quenched with water (0.5 mL) and then concentratedin vacuo to give a residue. The residue was purified by reversed phasechromatography (0.1% NH₃ H₂O) to give the title compound (130 mg, 22%yield) as a yellow oil. LC-MS (ESI⁺) m/z 519.4 (M+Na)⁺.

Step 7—Tert-ButylN-[2-[2-[2-(3-amino-2-fluoro-propoxy)-1-methyl-ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]-1-methyl-ethoxy]ethoxy]ethyl]carbamate (0.3 g, 578 umol) in MeOH (10 mL) and NH₃ H₂O (1 mL) wasadded Pd(OH)₂/C (0.2 g, 10 wt %) and Pd/C (0.2 g, 10 wt %), and themixture was stirred at rt for 12 h under hydrogen atmosphere (15 psipressure). On completion, the reaction mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (140 mg,71% yield) as a colorless oil. LC-MS (ESI⁺) m/z 339.2 (M+H)⁺.

2-[2-[2-[2-(3-Amino-2-fluoro-propoxy)ethoxy]ethoxy]propyl]isoindoline-1,3-dione(Intermediate BU)

Step 1—1-Benzyloxypropan-2-ol

To a solution of LiAlH₄ (7.56 g, 199 mmol) in anhydrous tetrahydrofuran(100 mL) was added a solution of 2-(benzyloxymethyl)oxirane (21.8 g, 132mmol, 20.1 mL) in anhydrous tetrahydrofuran (300 mL) dropwise at 0° C.under nitrogen atmosphere. The mixture was then stirred for 1 hour. Oncompletion, the reaction mixture was quenched with water (15 mL), then15% sodium hydroxide solution (15 mL) was added, and the mixture wasstirred for a further 15 minutes until no precipitate formed. Next, theinorganic salt precipitate was filtered off and the filter cake waswashed with ethyl acetate (2×100 mL). The combine organic phase wasdried over anhydrous magnesium sulfate, filtered and concentrated invacuo to give a residue. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=2:1) to give the titlecompound (21.3 g, 96% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 7.40-7.29 (m, 5H), 4.57 (s, 2H), 4.08-3.94 (m, 1H), 3.49 (dd, J=3.2,9.2 Hz, 1H), 3.30 (dd, J=8.4, 9.2 Hz, 1H), 2.40 (d, J=2.4 Hz, 1H), 1.16(d, J=6.4 Hz, 3H).

Step 2—2-[2-(2-Bromoethoxy)ethoxy]propoxymethylbenzene

A mixture of 1-benzyloxypropan-2-ol (4.00 g, 24.0 mmol),1-bromo-2-(2-bromoethoxy)ethane (27.9 g, 120 mmol, 15.0 mL),tetrabutylammonium bromide (7.76 g, 24.0 mmol), potassium iodide (3.99g, 24.0 mmol) and sodium hydride (2.89 g, 72.2 mmol, 60% dispersion inmineral oil) in N,N-dimethylformamide (40 mL) was degassed and purgedwith nitrogen gas three times. Then the mixture was stirred at rt for 20hours under nitrogen atmosphere. On completion, the reaction mixture waspoured into ice water (100 mL) and extracted with ethyl acetate (3×100mL). The combined organic phase was dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to get a residue. The residue waspurified by column chromatography (petroleum ether:ethyl acetate=6:1) togive the title compound (4.20 g, 55% yield) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 7.40-7.25 (m, 5H), 4.58 (s, 2H), 3.83 (t, J=6.4 Hz,2H), 3.75-3.66 (m, 5H), 3.56-3.42 (m, 4H), 1.20 (d, J=6.4 Hz, 3H).

Step3—N,N-dibenzyl-3-[2-[2-(2-benzyloxy-1-methyl-ethoxy)ethoxy]ethoxy]-2-fluoro-propan-1-amine

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (2.00 g, 7.32mmol, Intermediate AH) in N,N-dimethylformamide (40 mL) was added sodiumhydride (878 mg, 21.9 mmol, 60% dispersion in mineral oil) at 0° C. andthe reaction was stirred for 30 minutes. Then2-[2-(2-bromoethoxy)ethoxy]propoxy-methylbenzene (2.50 g, 7.88 mmol) wasadded and the reaction mixture was then allowed to warm to rt andstirred for a further 15.5 hours. On completion, the reaction mixturewas quenched with ice water (120 mL) and extracted with ethyl acetate(3×50 mL). The organic phase was collected, dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to get a residue. Theresidue was purified by column chromatography (petroleum ether:ethylacetate=4:1) to give the title compound (2.60 g, 69% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.34 (m, 15H), 4.91-4.71(m, 1H), 4.59 (d, J=2.4 Hz, 2H), 3.74-3.60 (m, 16H), 3.48-3.42 (m, 1H),2.81-2.72 (m, 2H), 1.21 (d, J=6.4 Hz, 3H).

Step 4—2-[2-[2-(3-Amino-2-fluoro-propoxy)ethoxy]ethoxy]propan-1-ol

To a solution ofN,N-dibenzyl-3-[2-[2-(2-benzyloxy-1-methyl-ethoxy)ethoxy]ethoxy]-2-fluoro-propan-1-amine(2.30 g, 4.51 mmol) in methanol (30 mL) was added Pd/C (1.00 g, 10 wt %)and Pd(OH)₂/C (1.00 g, 10 wt %) under nitrogen gas atmosphere. Thesuspension was degassed under vacuum and purged with hydrogen gasseveral times. The mixture was stirred under hydrogen gas (50 psipressure) at rt for 18 h. On completion, the reaction mixture wasfiltered through a pad of celite and the pad and the filter cake waswashed with methanol (3×10 mL). The filtration was concentrated in vacuoto give the crude product (930 mg, 86% yield) as a colorless oil. LC-MS(ESI)⁺ m/z 240.0. (M+H)⁺.

Step 5—Tert-butylN-[2-fluoro-3-[2-[2-(2-hydroxy-1-methyl-ethoxy)ethoxy]ethoxy]propyl]carbamate

To a solution of2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]propan-1-ol (850 mg,3.55 mmol) in dichloromethane (30 mL) was added Boc₂0 (852 mg, 3.91mmol, 897 uL) dropwise. The mixture was stirred at rt for 2 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by silica gel column chromatography(petroleum ether:ethyl acetate=0:1) to give the title compound (930 mg,77% yield) as a colorless gum. ¹H NMR (400 MHz, CDCl₃) δ 5.28 (m, 1H),4.83-4.60 (m, 1H), 3.87-3.79 (m, 1H), 3.73-3.58 (m, 11H), 3.50-3.36 (m,3H), 3.13 (br s, 1H), 1.45 (s, 9H), 1.13 (d, J=6.4 Hz, 3H).

Step6—2-[2-[2-[3-(Tert-butoxycarbonylamino)-2-fluoro-propoxy]ethoxy]ethoxy]propylmethane-sulfonate

To a solution of tert-butylN-[2-fluoro-3-[2-[2-(2-hydroxy-1-methyl-ethoxy)ethoxy]ethoxy]propyl]-carbamate(880 mg, 2.59 mmol) in dichloromethane (30 mL) was added triethylamine(787 mg, 7.78 mmol, 1.08 mL) and the reaction mixture was cooled to 0°C. Then methylsulfonyl chloride (445 mg, 3.89 mmol, 301 uL) was addeddropwise at 0° C. Then, the mixture was allowed to warm to rt andstirred for 30 minutes. On completion, the reaction mixture was quenchedwith ice water (30 mL), The organic phase was separated, washed withcitric acid (30 mL), then dried over anhydrous magnesium, filtered andconcentrated in vacuo to give the title compound (1.00 g, 92% yield) asa colorless gum. ¹H NMR (400 MHz, CDCl₃) δ 4.97 (m, 1H), 4.80-4.60 (m,1H), 4.24-4.12 (m, 2H), 3.82-3.61 (m, 11H), 3.47-3.28 (m, 2H), 3.08 (s,3H), 1.45 (s, 9H), 1.22 (d, J=6.4 Hz, 3H).

Step 7—Tert-ButylN-[3-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethoxy]ethoxy]ethoxy]-2-fluoro-propyl]carbamate

To a solution of2-[2-[2-[3-(tert-butoxycarbonylamino)-2-fluoro-propoxy]ethoxy]ethoxy]propylmethanesulfonate (1.00 g, 2.40 mmol) in N,N-dimethylformamide (20 mL)was added (1,3-dioxoiso-indolin-2-yl)potassium (532 mg, 2.87 mmol). Themixture then heated to 80° C. and stirred for 16 h. On completion, thereaction mixture was concentrated in vacuo to get a residue. The residuewas diluted in ice water (20 mL) and extracted with ethyl acetate (3×15mL). The organic phase was collected, dried over anhydrous magnesiumsulfate, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by silica gel column chromatography(petroleum ether:ethyl acetate=3:1) to give the title compound (730 mg,65% yield) as a colorless gum. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (m, 2H),7.65 (m, 2H), 4.91 (m, 1H), 4.70-4.49 (m, 1H), 3.81-3.70 (m, 2H),3.66-3.42 (m, 12H), 3.30-3.18 (m, 1H), 1.37 (s, 9H), 1.14 (d, J=6.4 Hz,3H).

Step8—2-[2-[2-[2-(3-Amino-2-fluoro-propoxy)ethoxy]ethoxy]propyl]isoindoline-1,3-dione

To a solution of tert-butylN-[3-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethoxy]ethoxy]ethoxy]-2-fluoro-propyl]carbamate(350 mg, 747 umol) in dichloromethane (14 mL) was added a solution ofhydrochloric acid in dioxane (4 M, 14 mL). The mixture was stirred at rtfor 30 minutes. On completion, the reaction mixture was concentrated invacuo to give the title compound (300 mg, 99% yield, hydrochloride salt)as a colorless gum. LC-MS (ESI)⁺ m/z 369.1. (M+H)⁺.

Tert-Butyl N-[3-[3-(3-amino-2-fluoro-propoxy)propoxy]propyl]carbamate(Intermediate BV)

Step 1—3-(3-Hydroxypropoxy)propanenitrile

To a mixture of propane-1,3-diol (28.7 g, 377 mmol, 27.3 mL) andprop-2-enenitrile (20.0 g, 377 mmol, 25.0 mL) was added NaOMe (204 mg,3.77 mmol). The mixture was stirred at rt for 20 h. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by silica column chromatography to give the titlecompound (20.3 g, 41% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 3.70 (t, J=6.0 Hz, 2H), 3.65-3.57 (m, 4H), 2.55 (t, J=6.4 Hz, 2H),1.99 (s, 1H), 1.79 (m, 2H).

Step 2—Tert-butyl N-[3-(3-hydroxypropoxy)propyl]carbamate

To a solution of 3-(3-hydroxypropoxy)propanenitrile (5.00 g, 38.7 mmol)in MeOH (50 mL) was added Raney-Ni (1.00 g) and (Boc)₂O (12.7 g, 13.3mL) under nitrogen atmosphere. The suspension was degassed and purgedwith hydrogen gas three times. The mixture was stirred under hydrogenatmosphere (50 psi pressure) at rt for 72 h. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo to give aresidue. The residue was purified by silica column chromatography togive the title compound (6.5 g, 72% yield) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 4.86 (s, 1H), 3.79 (t, J=5.6 Hz, 2H), 3.60 (t, J=6.0Hz, 2H), 3.50 (t, J=6.0 Hz, 2H), 3.30-3.18 (m, 2H), 2.63 (s, 1H),1.87-1.70 (m, 4H), 1.45 (s, 9H).

Step 3—3-[3-(Tert-butoxycarbonylamino)propoxy]propyl methanesulfonate

To a solution of tert-butyl N-[3-(3-hydroxypropoxy)propyl]carbamate(1.20 g, 5.14 mmol) in DCM (10 mL) was added Et₃N (1.56 g, 2.15 mL, 15.4mmol) and MsCl (884 mg, 7.72 mmol). The mixture was stirred at rt for 2h. On completion, the reaction was quenched with water (10 mL) andextracted with DCM (2×30 mL). The organic layer was washed with brine(20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuoto give the title compound (1.60 g, 99% yield) as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 4.88-4.78 (s, 1H), 4.36 (t, J=6.0 Hz, 2H), 3.52 (m,4H), 3.27-3.19 (m, 2H), 3.03 (s, 3H), 2.01 (t, J=6.0 Hz, 2H), 1.76 (t,J=6.0 Hz, 2H), 1.45 (s, 9H).

Step 4—Tert-ButylN-[3-[3-(3-amino-2-fluoro-propoxy)propoxy]propyl]carbamate

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (1.00 g, 3.66mmol, Intermediate AH) in DMF (20 mL) was added NaH (439 mg, 11.0 mmol,60% dispersion in mineral oil) and the reaction mixture was stirred for30 minutes at rt. Then, 3-[3-(tert-butoxycarbonylamino) propoxy]propylmethanesulfonate (1.48 g, 4.76 mmol) was added and the mixture wasstirred at rt for an additional 12 h. On completion, the mixture wasquenched with saturated NH₄Cl solution and extracted with EA (3×50 mL).The organic layer was dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by reversed phase chromatography (0.1%NH3·H2O in water) to give the title compound (800 mg, 45% yield). LC-MS(ESI⁺) m/z 489.4 (M+H)⁺.

Step 5—Tert-ButylN-[3-[3-(3-amino-2-fluoro-propoxy)propoxy]propyl]carbamate

To a solution of tert-butylN-[3-[3-[3-(dibenzylamino)-2-fluoro-propoxy]propoxy]propyl]carbamate(600 mg, 1.23 mmol) in MeOH (10 mL) was added Pd/C (200 mg, 10 wt %) andPd(OH)₂/C (200 mg, 10 wt %) under nitrogen atmosphere. The suspensionwas degassed and purged with hydrogen gas three times. The mixture wasstirred under hydrogen atmosphere (50 psi pressure) at rt for 18 h. Oncompletion, the mixture was filtered and concentrated in vacuo to givethe title compound (370 mg, 98% yield) as a white gum. LC-MS (ESI⁺) m/z309.0 (M+H)⁺.

Methyl2-[2-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate(Intermediate BW)

Step 1—Ethyl2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture 2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethanol(14.0 g, 58.7 mmol, CAS #4792-15-8) and BF₃ Et₂O (833 mg, 5.88 mmol) inDCM (200 mL) was added dropwise ethyl 2-diazoacetate (6.70 g, 58.7 mmol)in DCM (100 mL) at rt under nitrogen atmosphere. The reaction mixturewas stirred at rt for 12 hours. On completion, the reaction mixture wasconcentrated in vacuo. The residue was purified by flash chromatography(DCM/MeOH=100/1) to give the title compound (5.00 g, 26% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.20 (q, J=7.2 Hz, 2H), 4.14(s, 2H), 3.75-3.62 (m, 18H), 3.62-3.58 (m, 2H), 2.69 (s, 1H), 1.27 (t,J=7.2 Hz, 3H).

Step 2—Ethyl2-[2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of ethyl2-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (5.00g, 15.4 mmol) in DCM (50 mL) was added TEA (4.68 g, 46.2 mmol) and thereaction was cooled to 0° C. Then MsCl (2.12 g, 18.4 mmol) was addeddropwise at 0° C. and the reaction mixture was allowed to warm to rt andstirred for 3 hours. On completion, the reaction mixture was dilutedwith water (30 mL) and extracted with DCM (3×50 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (6.60 g, 95% yield) as a light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 4.39-4.35 (m, 2H), 4.20 (q, J=7.2 Hz,2H), 4.14 (s, 2H), 3.79-3.60 (m, 18H), 3.08 (s, 3H), 1.27 (t, J=7.2 Hz,3H).

Step3—2-[2-[2-[2-[2-[2-[3-(Dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a mixture of 3-(dibenzylamino)-2-fluoro-propan-1-ol (67.9 mg, 248umol, Intermediate AH) in DMF (4 mL) was added NaH (14.9 mg, 372 umol,60% dispersion in mineral oil) at 0° C. Then, the reaction mixture wasallowed to warm to rt and stirred for 0.5 hour. Then ethyl2-[2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (100 mg, 248 umol) was added and the reaction mixture wasstirred at rt for an additional 12 hours. On completion, the reactionmixture was concentrated in vacuo. The residue was diluted with water(10 mL) and extracted with EA (2×20 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by prep-TLC (DCM/MeOH=10/1) to givethe title compound (64.0 mg, 46% yield) as a colorless oil. LC-MS (ESI)⁺m/z 552.2. (M+H)⁺.

Step 4—Methyl2-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of2-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (2.10 g, 3.81 mmol) in MeOH (20 mL) was added SOCl₂(3.28 g, 27.5 mmol). The reaction mixture was stirred at rt for 38hours. On completion, the reaction mixture was filtered and concentratedin vacuo to give a residue. The residue was diluted with water (10 mL)and extracted with DCM (4×30 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel column chromatography to give thetitle compound (550 mg, 25% yield) as a light yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.30-7.21 (m, 8H), 7.18-7.13 (m, 2H), 4.10 (s, 2H),3.69-3.60 (m, 8H), 3.60-3.51 (m, 22H), 2.68 (d, J=5.6 Hz, 1H), 2.63 (d,J=5.2 Hz, 1H).

Step 5—Methyl2-[2-[2-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of methyl2-[2-[2-[2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate (10.0 mg, 17.6 umol) in EtOH (1 mL) was added TFA(15.4 mg, 10.0 uL, 135 umol) and Pd(OH)₂/C (20.0 mg, 10 wt %) underhydrogen atmosphere (15 psi pressure). The reaction mixture was stirredat rt for 12 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was diluted with water (8 mL) andextracted with EA (3×15 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(6.00 mg, 88% yield) as a light yellow oil. LC-MS (ESI)⁺ m/z 386.2.(M+H)⁺.

Methyl 2-(2-(2-(3-amino-2-fluoropropoxy)ethoxy)ethoxy)acetate(Intermediate BX)

Step 1—2-[2-[2-[3-(Dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]aceticAcid

To a solution of 3-(dibenzylamino)-2-fluoro-propan-1-ol (1.5 g, 5.49mmol, Intermediate AH) in DMF (20 mL) was added NaH (658 mg, 60%dispersion in mineral oil) at rt. After stirred for 30 minutes, ethyl2-[2-(2-methylsulfonyloxyethoxy)ethoxy]acetate (1.93 g, 7.13 mmol,synthesized via Steps 1-2 of Intermediate BM) was added and the mixturewas stirred at rt for 12 h. On completion, the mixture was poured intowater (60 mL) and extracted with EA (3×50 mL). The organic layer waswashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (2.00 g, 40% yield).LC-MS (ESI⁺) m/z 420.1 (M+H)⁺.

Step 2—Methyl2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]acetate

A mixture of2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]acetic acid(2.00 g, 4.77 mmol), SOCl₂ (24.6 g, 15 mL) and MeOH (20 mL) was stirredat 70° C. for 1 hour under nitrogen atmosphere. On completion, thereaction mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography (DCM:MeOH=100: 1 to 20: 1) to give the titlecompound (900 mg, 39% yield) as a red oil. LC-MS (ESI⁺) m/z 434.1(M+H)⁺.

Step 3—Methyl 2-(2-(2-(3-amino-2-fluoropropoxy)ethoxy)ethoxy)acetate

To a solution of methyl2-[2-[2-[3-(dibenzylamino)-2-fluoro-propoxy]ethoxy]ethoxy]acetate (1.00g, 2.31 mmol) in MeOH (20 mL) was added Pd(OH)₂/C (100 mg, 10 wt %),Pd/C (100 mg, 10 wt %) and acetic acid (0.1 mL) under nitrogenatmosphere. The suspension was degassed and purged with hydrogen gasthree times. The mixture was stirred under hydrogen atmosphere (50 psipressure) at rt for 24 hrs. On completion, the mixture was filtered andthe filtrate was concentrated in vacuo. The residue was dissolved in DCM(10 mL) and HCl (4M in EA, 5 mL) was added. The mixture was trituratedwith MTBE (100 mL) and the white solid was collected to give the titlecompound (400 mg, 60% yield). LC-MS (ESI⁺) m/z 254.0 (M+H)⁺.

6-(1,3-Benzothiazol-6-ylamino)-4-(cyclopropylamino)pyridine-3-carboxylicAcid (Intermediate BY)

Step 1—Ethyl 6-chloro-4-(cyclopropylamino)pyridine-3-carboxylate

To a mixture of ethyl 4,6-dichloropyridine-3-carboxylate (30.0 g, 136mmol) in DMA (300 mL) was added DIPEA (17.6 g, 136 mmol) andcyclopropanamine (8.56 g, 149 mmol). The reaction mixture was heated to90° C. and stirred for 3 h. On completion, the reaction mixture wasquenched with crushed ice. The resulting slurry was stirred andfiltered. The filter cake was purified by flash chromatography(PE/EA=3/1) to give the title compound (28.4 g, 86% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.53 (s, 1H), 8.08 (s, 1H), 7.02 (s,1H), 4.30 (q, J=7.2 Hz, 2H), 2.63-2.57 (m, 1H), 1.30 (t, J=7.2 Hz, 3H),0.87-0.84 (m, 2H), 0.58-0.56 (m, 2H).

Step 2—Ethyl6-(1,3-benzothiazol-6-ylamino)-4-(cyclopropylamino)pyridine-3-carboxylate

To a solution of ethyl6-chloro-4-(cyclopropylamino)pyridine-3-carboxylate (5.00 g, 20.7 mmol)in a mixed solvent of dioxane (30.0 mL) and H₂O (5.00 mL) was added1,3-benzothiazol-6-amine (3.12 g, 20.7 mmol), Xantphos (4.81 g, 8.31mmol) and Na₂CO₃ (8.81 g, 83.1 mmol), followed by Pd₂(dba)₃ (7.61 g,8.31 mmol) to the reaction mixture under nitrogen. The reaction mixturewas then heated at 115° C. for 12 h. On completion, the reaction mixturewas diluted with water (100 mL) and extracted with DCM (2×100 mL). Theorganic layer was dried with Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography (DCM:MeOH=100:1)to give the title compound (0.60 g, 6% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 8.91 (s, 1H), 8.68 (s, 1H), 8.13 (d, J=2.0 Hz, 1H),8.09 (d, J=8.8 Hz, 2H), 7.43 (dd, J=2.0, 8.8 Hz, 1H), 6.89-6.84 (m, 1H),6.46 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 2.45-2.36 (m, 1H), 1.38 (t, J=7.2Hz, 3H), 0.80-0.74 (m, 2H), 0.62-0.57 (m, 2H).

Step3—6-(1,3-Benzothiazol-6-ylamino)-4-(cyclopropylamino)pyridine-3-carboxylicAcid

To a solution of ethyl6-(1,3-benzothiazol-6-ylamino)-4-(cyclopropylamino)pyridine-3-carboxylate(0.43 g, 1.21 mmol) in a mixed solvent of H₂O (1.00 mL) and THF (3.00mL) was added LiOH H₂O (152 mg, 3.64 mmol). The reaction mixture wasstirred at 40° C. for 24 h. On completion, the reaction was acidifiedwith 2 N HCl until pH=4. The reaction mixture was then concentrated invacuo and lyophilized to give the title compound (500 mg, 79% yield, HClsalt) as a white solid. LC-MS (ESI⁺) m/z 327.0 (M+H)⁺.

6-[(5-Cyano-3-fluoro-2-pyridyl)amino]-4-(cyclopropylamino)pyridine-3-carboxylicAcid (Intermediate BZ)

Step 1—6-Amino-5-fluoro-pyridine-3-carbonitrile

To a solution of 5-bromo-3-fluoro-pyridin-2-amine (5.00 g, 26.1 mmol),potassium ferrocyanide (3.86 g, 10.4 mmol) and Pd(PPh₃)₄ (1.51 g, 1.31mmol) in a mixed solvent of t-BuOH (40.0 mL) and H₂O (40.0 mL) was addedDBU (996 mg, 6.54 mmol, 986 uL) under nitrogen. The reaction mixture washeated to 85° C. and stirred for 16 h. On completion, the mixture wasdiluted with water (20.0 mL) and extracted with EA (3×20 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (PE:EA=5:1) to give the title compound (2.50 g, 69%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.85(dd, J=1.6, 11.6 Hz, 1H), 7.38 (s, 2H).

Step 2—Ethyl6-[(5-cyano-3-fluoro-2-pyridyl)amino]-4-(cyclopropylamino)pyridine-3-carboxylate

To a solution of 6-amino-5-fluoro-pyridine-3-carbonitrile (2.50 g, 18.2mmol), ethyl 6-chloro-4-(cyclopropylamino)pyridine-3-carboxylate (4.39g, 18.2 mmol, synthesized via Step 1 of Intermediate BY) and Na₂CO₃(7.73 g, 72.9 mmol) in a mixed solvent of dioxane (40.0 mL) and H₂O(8.00 mL) was added Xantphos (527 mg, 911 umol) and Pd₂(dba)₃ (834 mg,911 umol) under nitrogen. The reaction mixture was then heated to 115°C. and stirred for 16 h. On completion, the mixture was diluted with amixed solvent of DCM and MeOH (80.0 mL, 10:1), and stirred for 1 h, thenfiltered. The solid was washed with water (50 mL) and triturated with amixed solvent of DCM and MeOH (30 mL, 10:1) to give the title compound(2.20 g, 35% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.83(s, 1H), 8.62 (d, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.21 (dd, J=1.6, 11.2 Hz,1H), 8.05-7.98 (m, 2H), 4.27 (q, J=7.2 Hz, 2H), 2.55-2.54 (m, 1H), 1.31(t, J=7.2 Hz, 3H), 0.95-0.86 (m, 2H), 0.60-0.55 (m, 2H).

Step3—6-[(5-Cyano-3-fluoro-2-pyridyl)amino]-4-(cyclopropylamino)pyridine-3-carboxylicAcid

To a solution of ethyl6-[(5-cyano-3-fluoro-2-pyridyl)amino]-4-(cyclopropylamino)pyridine-3-carboxylate(500 mg, 1.46 mmol) in a mixed solvent of THF (3.00 mL), MeOH (1.00 mL)and H₂O (1.00 mL) was added LiOH H₂O (307 mg, 7.32 mmol). The reactionmixture was stirred at 45° C. for 2 hrs. On completion, the mixture wasacidified with 1N HCl until the pH=3. The mixture was lyophilized togive the title compound (800 mg, 80% yield) as a yellow solid. LC-MS(ESI⁺) m/z 314.0 (M+H)⁺.

2-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetic Acid(Intermediate CA)

Step 1—2-(2,6-Dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione

To a solution of 4-hydroxyisobenzofuran-1,3-dione (20.0 g, 122 mmol) inpyridine (100 mL) was added 3-aminopiperidine-2,6-dione (20.0 g, 122mmol, HCl salt). The reaction mixture was stirred at 110° C. for 16 h.On completion, the mixture was concentrated in vacuo. The residue wasdiluted with water (500 mL) and stirred for 16 h. The mixture was thenfiltered and the filter cake was dried in vacuo to give the titlecompound (24.8 g, 74% yield) as a white solid. LC-MS (ESI⁺) m/z 297.0(M+Na)⁺.

Step 2—Tert-Butyl2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetate

To a mixture of2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione (20 g, 72.9mmol) and tert-butyl 2-chloroacetate (16.5 g, 109 mmol) in DMF (50 mL)was added Ag₂0 (16.9 g, 72.9 mmol), K₂CO₃ (25.2 g, 182 mmol) and KI(1.21 g, 7.29 mmol). The reaction mixture was stirred at rt for 12 h. Oncompletion, the reaction mixture was filtered and the filtrate wasdiluted with H₂O (40 mL) and extracted with DCM (2×200 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by silica gel chromatography to give the titlecompound (2.40 g, 8.5% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.13 (s, 1H), 7.84-7.78 (m, 1H), 7.49 (d, J=7.2 Hz, 1H),7.38 (d, J=8.8 Hz, 1H), 5.12 (dd, J=5.2, 12.8 Hz, 1H), 4.98 (s, 2H),2.60-2.54 (m, 1H), 2.52-2.50 (m, 2H), 2.10-2.01 (m, 1H), 1.43 (s, 9H).

Step 3—2-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyaceticAcid

To a mixture of tert-butyl2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetate (2.40g, 6.18 mmol) in DCM (10 mL) was added TFA (61.5 g, 539 mmol). Then thereaction mixture was stirred at rt for 12 h. On completion, the reactionmixture was concentrated in vacuo to give the title compound (3.10 g,90% yield, TFA salt) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13(s, 1H), 7.80 (dd, J=7.2, 8.4 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 7.40 (d,J=8.4 Hz, 1H), 5.11 (dd, J=5.2, 12.8 Hz, 1H), 5.00 (s, 2H), 2.95-2.84(m, 1H), 2.64-2.53 (m, 2H), 2.11-1.98 (m, 1H); LC-MS (ESI⁺) m/z 332.9(M+H)⁺.

(3S,4S,5S)-4-Ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(Intermediate CB)

Step 1—(S)-3,3-Dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one

To a mixture of (5S)-5-(hydroxymethyl)pyrrolidin-2-one (200 g, 1.74 mol)and 2,2-dimethoxypropane (517 g, 4.97 mol) in toluene (2.4 L) was addedTsOH-H₂O (13.2 g, 69.5 mmol). The reaction mixture was then stirred at120° C. for 16 h. On completion, the reaction mixture was concentratedin vacuo and diluted with EA (5 L). The mixture was washed with 1N NaOHsolution (2 L) and extracted with EA (8×1L). The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo. The residue wastriturated with PE (200 mL) to give the title compound (200 g, 74%yield) as a black brown crystal. ¹H NMR (400 MHz, CDCl₃) δ 4.29-4.19 (m,1H), 4.05 (dd, J=5.6, 8.4 Hz, 1H), 3.42 (t, J=8.4 Hz, 1H), 2.81-2.71 (m,1H), 2.58-2.44 (m, 1H), 2.21-2.08 (m, 1H), 1.82-1.66 (m, 1H), 1.68 (s,3H), 1.47 (s, 3H).

Step2—(S)-3,3-Dimethyl-5-((trimethylsilyl)oxy)-1,3,7,7a-tetrahydropyrrolo[1,2-c]oxazole

To a solution of DIPA (119 g, 1.18 mol) in THF (1.3 mL) was added n-BuLi(2.5 M, 433 mL) at −25° C. The reaction mixture was stirred for 30 min.Then, the reaction mixture was cooled to −70° C. A solution of(S)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (140 g, 902mmol) in THF (500 mL) was added dropwise. The reaction mixture wasstirred at −60° C. for 5 min. Then, TMSCl (127 g, 1.17 mmol) was addeddropwise at −60° C. The reaction mixture was allowed to warm to −10° C.and stirred for 25 min. On completion, the reaction mixture wasconcentrated in vacuo. The residue was triturated with hexane (1 L),filtered and the filtrate was concentrated in vacuo to give the titlecompound (140 g, 68% yield) as a colorless oil. The product was unstableand was used for the next step directly without purification.

Step 3 (7aS)-3,3-dimethyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5-one

To a mixture of(S)-3,3-dimethyl-5-((trimethylsilyl)oxy)-1,3,7,7a-tetrahydropyrrolo[1,2-c]oxazole(140 g, 616 mmol) and allyl methyl carbonate (107 g, 923 mmol) in THF(1.4 L) was added Pd(OAc)₂ (41.5 g, 185 mmol). The reaction mixture wasstirred at 65° C. for 8 h under nitrogen. On completion, the reactionmixture was concentrated in vacuo. The residue was purified by silicagel chromatography (PE:EA=5:1) to give the title compound (30 g, 32%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.00 (d, J=5.6 Hz,1H), 6.04 (d, J=5.6 Hz, 1H), 4.67-4.49 (m, 1H), 4.09-4.04 (m, 1H), 3.27(t, J=8.8 Hz, 1H), 1.61 (s, 3H), 1.50 (s, 3H).

Step4—(7R,7aS)-7-Ethyl-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one

To a mixture of bromocopper-methylsulfanylmethane (14.1 g, 68.6 mmol) inTHF (200 mL) was added EtMgBr (3 M, 45.7 mL) at −10° C. dropwise. Then,the reaction mixture was cooled to −70° C. and TMSCl (7.45 g, 68.6 mmol)was added dropwise over 15 min. The reaction mixture was then stirred at−70° C. for an additional 15 min. Then a solution of(7aS)-3,3-dimethyl-1,7a-dihydropyrrolo[1,2-c]oxazol-5-one (6.00 g, 27.4mmol) in THF (20 mL) was added dropwise over 10 min. Then the reactionmixture was stirred at 0° C. for 20 min. On completion, the reactionmixture was poured into cool saturated NH₄Cl solution (100 mL) andextracted with EA (3×500 mL). The combined layer was dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (PE:EA=3:1) to give the title compound (3 g, 60%yield). ¹H NMR (400 MHz, CDCl₃) δ 4.34 (td, J=6.4, 9.6 Hz, 1H), 3.90(dd, J=6.4, 8.4 Hz, 1H), 3.72 (dd, J=8.4, 9.6 Hz, 1H), 2.91 (dd, J=8.0,16.8 Hz, 1H), 2.31 (dd, J=1.6, 16.8 Hz, 1H), 2.28-2.18 (m, 1H), 1.64 (s,3H), 1.55-1.49 (m, 1H), 1.48 (s, 3H), 1.37-1.27 (m, 1H), 0.91 (t, J=7.2Hz, 3H).

Step5—(6S,7S,7aS)-7-Ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one

A solution of(7R,7aS)-7-ethyl-3,3-dimethyl-1,6,7,7a-tetrahydropyrrolo[1,2-c]oxazol-5-one(2.5 g, 13.6 mmol) in THF (10 mL) was treated at −78° C. with LiHMDS (1M, 15.0 mL) and the mixture was kept for 0.5 h at −78° C. A solution ofNFSI (5.60 g, 17.8 mmol) in THF (10 mL) was added slowly. The mixturewas kept at approximately −78° C. for 0.5 h. On completion, theprecipitated solid was filtered and washed with THF (20 mL). Thefiltrate was concentrated in vacuo to an oily residue. The oily residuewas purified by silica gel chromatography (PE:EA=10:1). Then, theresidue was repurified by reversed phase chromatography (0.1% FA) togive the title compound (575 mg, 21% yield) as a colorless oil. ¹H NMR(400 MHz, CD₃CN) 6 4.89-4.73 (m, 1H), 4.42 (td, J=6.4, 10.4 Hz, 1H),3.95 (dd, J=5.6, 8.4 Hz, 1H), 3.59 (dd, J=8.4, 10.4 Hz, 1H), 2.49-2.33(m, 1H), 1.59 (s, 3H), 1.58-1.51 (m, 1H), 1.45 (s, 3H), 1.44-1.37 (m,1H), 1.00 (t, J=7.2 Hz, 3H).

Step6—(6S,7S,7aS)-7-Eethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)

To a solution of diisopropylamine (322 mg, 3.18 mmol) in toluene (5 mL)was added n-BuLi (2.5 M, 1.26 mL) dropwise at −30° C. The mixture wasmaintained at −30° C. for an additional 30 min, then a solution of(6R,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyl-1,6,7,7a-tetrahydropyrrolo[1,2-c]oxazol-5-one(575 mg, 2.86 mmol) in toluene (2 mL) was added dropwise at −78° C. over2 h. After the addition was completed, the mixture was kept at −78° C.for 30 min more before a solution of BHT (1.30 g, 5.91 mmol) in toluene(2 mL) was added dropwise over 0.5 h, keeping the internal temperaturebelow −65° C. After the addition was completed, the mixture was kept at−78° C. for 30 min. The mixture was then warmed to rt and stirred for 2hrs. On completion, the reaction was quenched with water (5 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The residue was purified by silica gelchromatography (PE:EA=10:1) to give the title compound (244 mg, 40%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 5.36-5.15 (m, 1H),4.12-4.01 (m, 2H), 3.79-3.68 (m, 1H), 2.78-2.64 (m, 1H), 1.80-1.70 (m,1H), 1.69 (s, 3H), 1.50 (s, 3H), 1.42-1.32 (m, 1H), 0.98 (t, J=7.2 Hz,3H). LC-MS (ESI⁺) m/z 202.1 (M+H)⁺.

Step 7—(3S,4S,5S)-4-Ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one

(6S,7S,7aS)-7-ethyl-6-fluoro-3,3-dimethyl-1,6,7,7a-tetrahydropyrrolo[1,2-c]oxazol-5-one(330 mg, 1.64 mmol) in acetonitrile (1.5 mL) and H₂O (0.15 mL) wastreated with TFA (37.4 mg, 328 umol). The mixture was warmed to ˜65° C.over 1 h, and held at that temperature for 3 hrs. On completion, themixture was concentrated in vacuo. The residue was reversed phasechromatography to give the title compound (230 mg, 91% yield). ¹H NMR(400 MHz, CDCl₃) δ 7.59 (s, 1H), 4.80 (dd, 1H), 3.69-3.83 (m, 2H),3.52-3.64 (m, 1H), 3.48 (br. s, 1H), 2.27-2.52 (m, 1H), 1.57-1.73 (m,1H), 1.49 (dt, 1H), 1.04 (t, 3H). LC-MS (ESI⁺) m/z 162.1 (M+H)⁺

7-Methoxy-1-oxo-1,2-dihydroisoquinoline-6-carbonitrile (Intermediate CC)

Step 1—Methyl 4-iodo-3-methoxybenzoate

To a solution of 3-hydroxy-4-iodo-benzoic acid (25.0 g, 94.7 mmol) inacetone (350 mL) was added K₂CO₃ (52.4 g, 379 mmol) and CH₃I (53.8 g,379 mmol). The reaction mixture was stirred at 50° C. for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas dissolved with ethyl acetate (150 mL) and washed with water (150mL). The organic phase was dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give the title compound (24.5 g, 89% yield)as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8.0 Hz, 1H), 7.46(d, J=1.6 Hz, 1H), 7.38 (dd, J=1.6, 8.0 Hz, 1H), 3.95 (s, 3H), 3.93 (s,3H).

Step 2—4-Iodo-3-methoxybenzoic Acid

To a solution of methyl 4-iodo-3-methoxy-benzoate (3.00 g, 10.3 mmol) ina mixture of methanol (20 mL) and water (5 mL) was added LiOH·H2O (1.29g, 30.8 mmol). The reaction mixture was stirred at rt for 2 h. Oncompletion, the reaction mixture was concentrated in vacuo to remove themethanol. The aqueous phase was acidified with 2N HCl solution until thepH=2, and filtered. The filter cake was dried in vacuo to give the titlecompound (2.70 g, 95% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 13.21 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.30(dd, J=1.6, 8.0 Hz, 1H), 3.89 (s, 3H).

Step 3—N-(2,2-dimethoxyethyl)-4-iodo-3-methoxybenzamide

To a mixture of 4-iodo-3-methoxy-benzoic acid (2.3 g, 8.3 mmol), HATU(3.77 g, 9.93 mmol) and DIPEA (3.21 g, 24.8 mmol) in DMF (40 mL) wasadded 2,2-dimethoxyethanamine (1.04 g, 9.93 mmol). The reaction mixturewas stirred at rt for 1 h. On completion, the reaction mixture wasconcentrated in vacuo. The residue was diluted with water (40 mL),acidified with citric acid, and extracted with EA (3×100 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The crude product was purified by silica gel chromatography(PE/EA=1/2) to give the title compound (2.80 g, 93% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=8.0 Hz, 1H), 7.34 (d, J=2.0Hz, 1H), 6.99 (dd, J=2.0, 8.0 Hz, 1H), 6.33 (s, 1H), 4.49 (t, J=5.6 Hz,1H), 3.95 (s, 3H), 3.61 (t, J=5.6 Hz, 2H), 3.45 (s, 6H).

Step 4—6-Iodo-7-methoxyisoquinolin-1(2H)-one

A mixture of N-(2,2-dimethoxyethyl)-4-iodo-3-methoxy-benzamide (3.30 g,9.04 mmol) in concentrated H₂SO₄ (15 mL) was stirred at 60° C. for 0.5h. On completion, the reaction mixture was pour into ice water (200 mL)and extracted with DCM (3×200 mL). The combined organic layer was driedin vacuo to give the title compound (2.50 g, 92% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 8.22 (s, 1H), 7.54 (s,1H), 7.07 (d, J=7.2 Hz, 1H), 6.48 (d, J=7.2 Hz, 1H), 3.92 (s, 3H).

Step 5—7-Methoxy-1-oxo-1,2-dihydroisoquinoline-6-carbonitrile

A mixture of 6-iodo-7-methoxy-2H-isoquinolin-1-one (2.4 g, 7.97 mmol)and CuCN (2.14 g, 23.9 mmol) in DMF (50 mL) was stirred at 125° C. for 1h under nitrogen. On completion, the reaction mixture was concentratedin vacuo. The residue was dissolved in DCM:MeOH=10:1 (100 mL), filteredand concentrated in vacuo to give the title compound (1.40 g, 88% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.52 (s, 1H), 8.24 (s,1H), 7.78 (s, 1H), 7.17 (dd, J=5.6, 7.2 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H),4.02 (s, 3H).

1-(((2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carbonitrile(Intermediate CD)

Step 1—1-Chloro-7-methoxyisoquinoline-6-carbonitrile

To a mixture of 7-methoxy-1-oxo-2H-isoquinoline-6-carbonitrile (1.25 g,6.24 mmol, Intermediate CC) in dioxane (50 mL) was added POCl₃ (3.83 g,25.0 mmol). The reaction mixture was stirred at 110° C. for 2 h. Oncompletion, the reaction mixture was concentrated to remove the solvent.The residue was dissolved in DCM (20 mL) and washed with NaHCO₃ solutionuntil the pH=8. The reaction mixture was then extracted with DCM (3×100mL). The combined layer was dried over Na₂SO₄, filtered, and thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatography (PE:DCM=1:5) to give the title compound (1.00 g, 60%yield) as an off-white solid. LC-MS (ESI⁺) m/z 219.0 (M+H)⁺.

Step2—1-(((2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carbonitrile

A mixture of 1-chloro-7-methoxy-isoquinoline-6-carbonitrile (50.0 mg,229 umol) and(3S,4S,5S)-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one (36.9 mg,229 umol, Intermediate CB) were stirred in DMF (1 mL) and cooled toapproximately −10° C. A solution of KHMDS (1 M, 503.11 uL) in THF wasthen added into the reaction mixture over ˜15 minutes, maintaining theinternal reaction temperature at approximately −10° C. After, thereaction was stirred at −10° C. for approximately an additional 30minutes. On completion, the reaction mixture was quenched with saturatedNaH₂PO₄ (20 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed with brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by prep-TLC (EA) to give the title compound (50.0mg, 49% yield) as a white solid. LC-MS (ESI⁺) m/z 344.0 (M+H)⁺

1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxylicAcid (Intermediate CE)

Step 1—7-Methoxy-1-oxo-2H-isoquinoline-6-carboxylic Acid

To a solution of 7-methoxy-1-oxo-2H-isoquinoline-6-carbonitrile (1.50 g,7.49 mmol, Intermediate CC) in ethanol (30 mL) was added aqueous sodiumhydroxide (10 M, 15.0 mL). The mixture was stirred at 80° C. for 15 h.On completion, the reaction mixture was concentrated in vacuo to removethe ethanol. The residue was acidified with saturated citric acidaqueous until the pH<6. A fine light yellow precipitate formed and theprecipitate was filtered and dried in vacuo to give the title product(1.20 g, 73% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ13.16 (br s, 1H), 11.35 (br s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.10(dd, J=5.6, 6.8 Hz, 1H), 6.59 (d, J=7.2 Hz, 1H), 3.91 (s, 3H).

Step 2—Methyl 7-methoxy-1-oxo-2H-isoquinoline-6-carboxylate

To a solution of 7-methoxy-1-oxo-2H-isoquinoline-6-carboxylic acid (1.10g, 5.02 mmol) in methanol (50 mL) was added sulfonyl chloride (3.58 g,30.1 mmol, 2.18 mL). The mixture was stirred at 70° C. for 15 h. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was dissolved in ice water (30 mL) and basifiedwith saturated sodium bicarbonate aqueous until the pH>7 and a finelight yellow precipitate was formed. The precipitate was filtered anddried in vacuo to give the title compound (1.10 g, 93% yield) as a lightyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.79 (br s, 1H), 7.89 (s, 1H),7.83 (s, H), 7.03 (d, J=6.8 Hz, 1H), 6.49 (d, J=7.2 Hz, 1H), 3.96 (s,3H), 3.89 (s, 3H).

Step 3—Methyl 1-chloro-7-methoxy-isoquinoline-6-carboxylate

Methyl 7-methoxy-1-oxo-2H-isoquinoline-6-carboxylate (1.00 g, 4.29 mmol)was dissolved in POCl₃ (30 mL) and the mixture was stirred at 105° C.for 14 h. On completion, the reaction mixture was concentrated in vacuoto give a residue. The residue was dissolved in ice water (50 mL) andbasified with saturated sodium bicarbonate aqueous until the pH>7, and afine light yellow precipitate was formed. The precipitate was filteredand dried in vacuo to give the title compound (1.00 g, 92% yield) as alight yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=5.6 Hz, 1H),8.23 (s, 1H), 7.65 (s, 1H), 7.60 (d, J=5.6 Hz, 1H), 4.09 (s, 3H), 4.00(s, 3H).

Step 4—1-Chloro-7-methoxy-isoquinoline-6-carboxylic Acid

To a solution of methyl 1-chloro-7-methoxy-isoquinoline-6-carboxylate(1.00 g, 3.97 mmol) in a mixed solution of tetrahydrofuran (20 mL) andwater (10 mL) was added lithium hydroxide (380 mg, 15.8 mmol). Themixture was stirred at rt or 14 h. On completion, the reaction mixturewas concentrated in vacuo to remove the tetrahydrofuran. The resultingresidue was acidified with 1 N hydrochloride acid until the pH=6 and awhite precipitate was formed. The precipitate was filtered and thefilter cake was dried in vacuo to give the title compound (900 mg, 95%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (d, J=5.6 Hz,1H), 8.18 (s, 1H), 7.89 (d, J=5.6 Hz, 1H), 7.53 (s, 1H), 3.98 (s, 3H).

Step5—1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxylicAcid

A mixture of 1-chloro-7-methoxy-isoquinoline-6-carboxylic acid (200 mg,841 umol), (3S,4S,5S)-4-ethyl-3-fluoro-5-(hydroxymethyl)pyrrolidin-2-one(135 mg, 841 umol, Intermediate CB) in N,N-dimethylformamide (8 mL) wascooled to −10° C., and KHMDS (1 M, 3.53 mL) was added dropwise undernitrogen gas atmosphere to keep the temperature at −10° C. over 0.25 h.The mixture was stirred at 0° C. for 15 h. On completion, the reactionmixture was quenched with ice water (30 mL) and acidified with 1 Nhydrochloride acid until the pH=5, and then extracted withdichloromethane (3×15 mL). The combine organic phase was dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo to givea residue. The residue was purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]) to givethe title compound (95.0 mg, 28% yield, hydrochloride salt) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.13 (s, 1H), 7.92 (d,J=5.6 Hz, 1H), 7.74 (s, 1H), 7.43 (d, J=5.6 Hz, 1H), 4.99-4.82 (m, 1H),4.55 (dd, J=3.2, 11.2 Hz, 1H), 4.26 (dd, J=6.4, 11.2 Hz, 1H), 4.10-4.09(m, 1H), 3.94 (s, 3H), 2.69-2.55 (m, 1H), 1.66-1.56 (m, 2H), 1.02 (t,J=7.2 Hz, 3H).

2,2′-(Pentane-1,5-diylbis(oxy))diethanamine (Intermediate CF)

Step 1—Diethyl 2,2′-(pentane-1,5-diylbis(oxy))diacetate

To a solution of pentane-1,5-diol (20 g, 192 mmol, 20.2 mL) and Rh(OAc)₂(1.70 g, 7.68 mmol) in DCM (50 mL) was added a solution of ethyl2-diazoacetate (21.9 g, 192 mmol) in DCM (200 mL), and the reactionmixture was stirred at rt for 12 h. On completion, the reaction mixturewas diluted with water (100 mL) and extracted with DCM (2×200 mL). Thecombined organic phase was dried over Na₂SO₄, filtered and concentratedin vacuo to give a residue. The residue was purified by silica gelchromatography (PE/EA=5/1) to give the title compound (10 g, 19% yield)as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.24-4.20 (m, 4H), 4.05 (s,4H), 3.55-3.51 (m, 4H), 1.67-1.64 (m, 4H), 1.48-1.46 (m, 2H), 1.30-1.26(m, 6H).

Step 2—2,2′-(Pentane-1,5-diylbis(oxy))diethanol

To a solution of LAH (3.43 g, 90.5 mmol) in THF (100 mL) was addedslowly dropwise a solution of ethyl2-[5-(2-ethoxy-2-oxo-ethoxy)pentoxy]acetate (10.0 g, 36.2 mmol) in THF(100 mL) at 0° C. The reaction mixture was then allowed to warm to rtand stirred for 1 h under nitrogen. On completion, the reaction mixturewas quenched with water (6 mL) and 15% sodium hydroxide solution (10mL). Then, the mixture was filtered. The filtrate was concentrated invacuo to give the title compound (5.7 g, 83% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ 3.69-3.62 (m, 4H), 3.49-3.45 (m, 4H), 3.42 (t,J=6.0 Hz, 4H), 2.33 (t, J=6.0 Hz, 2H), 1.60-1.52 (m, 4H), 1.44-1.35 (m,2H).

Step 3-(Pentane-1,5-diylbis(oxy))bis(ethane-2,1-diyl) dimethanesulfonate

To a solution of 2-[5-(2-hydroxyethoxy)pentoxy]ethanol (5.7 g, 29.7mmol) in DCM (60 mL) was added TEA (9.00 g, 89.0 mmol) and MsCl (8.49 g,74.1 mmol). The reaction mixture was stirred at rt for 1 hr. Oncompletion, the reaction mixture was quenched with water (10 mL). Then,the mixture was washed with 1N citric aqueous (20 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give the title compound (10 g, 97% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ 4.45-4.33 (m, 4H), 3.76-3.68 (m, 4H), 3.51 (t,J=6.4 Hz, 4H), 3.08 (s, 6H), 1.67-1.60 (m, 4H), 1.48-1.41 (m, 2H).

Step4—2,2′-((Pentane-1,5-diylbis(oxy))bis(ethane-2,1-diyl))bis(isoindoline-1,3-dione)

A solution of 2-[5-(2-methylsulfonyloxyethoxy)pentoxy]ethylmethanesulfonate (10 g, 28.7 mmol) and(1,3-dioxoisoindolin-2-yl)potassium (11.7 g, 63.1 mmol) in DMF (100 mL)was heated to 100° C. for 12 h. On completion, the reaction mixture wasconcentrated in vacuo. The residue was dissolved ethyl acetate (300 mL)and filtered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatography (PE:EA=5:1) to give the titlecompound (11 g, 77% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.92-7.82 (m, 4H),7.77-7.72 (m, 4H), 3.88 (t, J=6.0 Hz, 4H), 3.64 (t, J=6.0 Hz, 4H), 3.39(t, J=6.4 Hz, 4H), 1.54-1.44 (m, 4H), 1.30-1.23 (m, 2H).

Step 5—2,2′-(Pentane-1,5-diylbis(oxy))diethanamine

To a solution of2-[2-[5-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]pentoxy]ethyl]isoindoline-1,3-dione(1.10 g, 2.44 mmol) in ethanol (20 mL) was added NH₂NH₂—H₂O (624 mg,12.2 mmol). The reaction mixture was stirred at 80° C. for 2 h. Oncompletion, the reaction mixture was cooled to rt and filtered. Thefiltrate was concentrated in vacuo. Then, the residue was diluted withDCM (20 mL) and filtered again. The filtrate was concentrated in vacuoto give the title compound (460 mg, 99% yield) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 3.51-3.43 (m, 8H), 2.87 (t, J=5.2 Hz, 4H),1.68-1.57 (m, 4H), 1.50-1.39 (m, 2H).

Tert-Butyl N-(11-aminoundecyl)carbamate (Intermediate CG)

To a mixture of undecane-1,11-diamine (512 mg, 2.75 mmol) in CHCl₃ (25mL) was added a solution of tert-butoxycarbonyl tert-butyl carbonate(120 mg, 549 umol) in CHCl₃ (5 mL) dropwise. The reaction mixture wasstirred at rt for 20 hours. On completion, the reaction mixture wasconcentrated in vacuo. The residue was purified by column chromatographyto give the title compound (120 mg, 76% yield) as a light yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 4.54 (s, 1H), 3.12 (d, J=6.0 Hz, 2H), 2.70 (t,J=7.0 Hz, 2H), 1.70-1.55 (m, 4H), 1.46 (s, 9H), 1.32-1.25 (m, 14H).

Ethyl2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetate(Intermediate CH)

Step 1—Ethyl 14-hydroxy-3,6,9,12-tetraoxatetradecan-1-oate

To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (10.0 g,51.5 mmol, CAS #112-60-7) in DCM (150 mL) was added BF₃ Et₂O (159 mg,515 umol) at 0° C. Then, ethyl 2-diazoacetate (5.87 g, 51.5 mmol) wasadded to the reaction mixture dropwise. After that, the mixture wasallowed to warm to rt and stirred for 12 hours. On completion, thereaction mixture was quenched by ammonium chloride (5 mL), then dilutedwith water (100 mL), and extracted with DCM (3×50 mL). The combinedorganic layers were dried over sodium sulfate and concentrated in vacuoto give a residue. The residue was purified by silica gel chromatographyto give the title compound (2.60 g, 18% yield) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 4.16 (q, J=7.2 Hz, 2H), 4.10 (s, 2H), 3.71-3.59(m, 14H), 3.58-3.54 (m, 2H), 1.24 (t, J=7.2 Hz, 3H).

Step 2—Ethyl2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate (6.86 g, 24.5mmol) in DCM (50 mL) was added TEA (4.95 g, 48.9 mmol). The reactionmixture was cooled to 0° C. Then MsCl (3.36 g, 29.4 mmol) was added intothe solution slowly. The reaction mixture was stirred at rt for 0.5hour. On completion, the reaction mixture was quenched with H₂O (20 mL)and saturated citric acid solution (20 mL) was added until the pH=5-6,then they organic layer was separated. The organic layer was washed withbrine (4×50 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound (8.00 g, 91% yield) as a brown oil. ¹H NMR(400 MHz, CDCl₃) δ 4.43-4.37 (m, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.16 (s,2H), 3.82-3.62 (m, 14H), 3.10 (s, 3H), 1.30 (t, J=7.2 Hz, 3H).

Step 3—Ethyl 2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate (8.00g, 22.3 mmol) in DMF (30 mL) was added NaN₃ (2.90 g, 44.6 mmol). Thereaction mixture was stirred at 80° C. for 15 h. On completion, thesolvent DMF was removed in vacuo. Then the residue was diluted with EA(150 mL) and filtered. The filtrate was used for the next step directlywithout further purification or concentration. LC-MS (ESI⁺) m/z 278.1(M+H-28)⁺.

Step 4—Ethyl2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethoxy]acetate (6.81 g, 22.3mmol) in EA (150 mL) was added Pd/C (700 mg, 10 wt %) and (Boc)₂O (24.3g, 112 mmol). The mixture was degassed and purged with hydrogen gasthree times. Then the reaction mixture was stirred at rt for 15 hours.On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (DCM/MeOH=10/1) to give the title compound(5.15 g, 61% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.05(s, 1H), 4.27 (q, J=7.2 Hz, 2H), 4.17 (s, 2H), 3.79-3.60 (m, 12H), 3.56(t, J=5.2 Hz, 2H), 3.37-3.27 (m, 2H), 1.45 (s, 9H), 1.31 (t, J=7.2 Hz,3H).

Step 5—Ethyl2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetate(0.40 g, 1.05 mmol) in THF (10 mL) and H₂O (4 mL) was added LiOH (50.5mg, 2.11 mmol). The reaction mixture was stirred at rt for 16 hours. Oncompletion, the mixture was concentrated in vacuo to give a residue,then diluted with H₂O. The aqueous phase was acidified with conc. HCluntil the pH=6 and concentrated in vacuo to give the title compound (350mg, 996 umol) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.18 (m, 2H),3.80-3.63 (m, 14H), 3.46-3.17 (m, 2H), 1.46-1.41 (s, 9H).

(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)-phenyl]methyl]pyrrolidine-2-carboxamide(Intermediate CI)

Step 1—4-(4-Methylthiazol-5-yl)benzonitrile

To a mixture of 4-bromobenzonitrile (32.0 g, 176 mmol), 4-methylthiazole(34.86 g, 352 mmol) and KOAc (34.5 g, 352 mmol) in DMA (100 mL) wasadded Pd(OAc)₂ (820 mg, 3.65 mmol). The mixture was stirred at 150° C.under nitrogen atmosphere for 2 hours. On completion, the mixture wasdiluted with water (200 mL) and extracted with ethyl acetate (3×200 mL).The combined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the crude product. The crude product wastriturated with PE (100 mL) and filtered to give the title compound(28.8 g, 82% yield) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.98(s, 1H), 7.85-7.81 (m, 2H), 7.71-7.66 (m, 2H), 2.53 (s, 3H); LC-MS(ESI⁺) m/z 201.0 (M+H)⁺.

Step 2—[4-(4-Methylthiazol-5-yl)phenyl]methanamine

To a solution of 4-(4-methylthiazol-5-yl)benzonitrile (14.7 g, 73.4mmol) in MeOH (460 mL) was added dichlorocobalt (14.3 g, 110 mmol) andthe mixture was cooled to 0° C. Then, NaBH₄ (13.9 g, 367 mmol) was addedin portions over 0.5 hour. Finally, the mixture was allowed to warm tort and stirred for 12 hours. On completion, the reaction mixture wasquenched with NH₃—H₂O (20 mL, 30 wt %), then diluted with water (100 mL)and extracted with DCM (3×80 mL). The combined organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by reverse phase flash column (0.1%NH₃·H₂O in water) to give the title compound (3.50 g, 23.3% yield) as ayellowish oil. LC-MS (ESI⁺) m/z 205.1 (M+H)⁺.

Step 3—Tert-Butyl(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]-pyrrolidine-1-carboxylate

A solution of(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid(3.36 g, 14.5 mmol, CAS #13726-69-7) in DMF (50 mL) was cooled to 0° C.Then, DIPEA (5.13 g, 39.7 mmol), [4-(4-methylthiazol-5-yl) phenyl]methanamine (2.70 g, 13.2 mmol) and HATU (6.03 g, 15.9 mmol) were added.Finally, the mixture was allowed to warm to rt and stirred for 12 hours.On completion, the reaction mixture was concentrated under reducedpressure to remove the DMF. The residue was diluted with water (50 mL)and extracted with DCM (3×60 mL). The combined organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by reverse phase flash (0.1% NH₃—H₂Oin water) column to give the title compound (1.70 g, 30% yield) as ayellowish solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.91 (s, 1H), 7.48-7.40 (m,4H), 4.74-4.25 (m, 4H), 3.66-3.56 (m, 1H), 3.54-3.43 (m, 1H), 2.48 (s,3H), 2.31-2.20 (m, 1H), 2.08-1.98 (m, 1H), 1.54-1.25 (m, 9H); LC-MS(ESI⁺) m/z 418.0 (M+H)⁺.

Step 4—(2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a solution of tert-butyl(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]-pyrrolidine-1-carboxylate(1.70 g, 4.07 mmol) in DCM (10 mL) was added HCl in dioxane (4 M, 10 mL)and the mixture was stirred at rt for 6 hours. On completion, themixture was concentrated under reduced pressure to give the product(1.60 g, HCl salt, 96% yield) as a yellowish solid. LC-MS (ESI⁺) m/z318.0 (M+H)⁺.

Step 5—Tert-ButylN-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamate

A solution of(2S,4R)-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(1.60 g, 4.52 mmol, HCl salt) in DMF (25.00 mL) was cooled to 0° C.Then, DIPEA (1.75 g, 13.6 mmol),(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (1.31 g,5.65 mmol) and HATU (2.06 g, 5.43 mmol) were added. Finally, the mixturewas allowed to warm to rt and stirred for 12 hours. On completion, thereaction mixture was concentrated under reduced pressure to remove theDMF. The residue was diluted with water (40 mL) and extracted with DCM(3×40 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by reverse phase flash column (0.1% NH₃H₂O in water) to givethe title compound (1.70 g, 70% yield) as a light yellow solid. ¹H NMR(400 MHz, CDCl₃-d₁) δ 8.71 (s, 1H), 7.43 (s, 1H), 7.39-7.30 (m, 4H),5.20 (d, J=8.0 Hz, 1H), 4.78 (t, J=1.6 Hz, 1H), 4.59 (m, 1H), 4.33 (m,1H), 4.18-4.09 (m, 2H), 3.58 (m, 1H), 2.60 (m, 1H), 2.52 (s, 3H), 2.14(m, 1H), 1.41 (s, 9H), 0.92 (s, 9H); LC-MS (ESI⁺) m/z 531.1 (M+H)⁺.

Step6—(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)-phenyl]methyl]pyrrolidine-2-carboxamide

To a solution of tert-butylN-[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]-methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamate (1.60 g,3.01 mmol) in DCM (20 mL) was added HCl in dioxane (4 M, 20 mL). Then,the mixture was stirred at rt for 6 hours. On completion, the mixturewas concentrated under reduced pressure to give the title compound as alight yellow solid (1.90 g, HCl salt, 95% yield). ¹H NMR (400 MHz,MeOD-d₄) δ 9.98 (s, 1H), 7.58-7.52 (m, 4H), 4.72-4.65 (m, 1H), 4.60-4.50(m, 2H), 4.46-4.38 (m, 1H), 4.07 (s, 1H), 3.86-3.83 (m, 1H), 3.75-3.68(m, 1H), 3.60 (s, 1H), 2.61 (s, 3H), 2.33-2.28 (m, 1H), 2.11-2.05 (m,1H), 1.14 (s, 9H); LC-MS (ESI⁺) m/z 431.1 (M+H)⁺.

4-Nitro-1H-pyrazole-5-carboxamide (Intermediate CJ)

A solution of ethyl 4-nitro-1H-pyrazole-5-carboxylate (6.00 g, 32.4mmol, CAS #55864-87-4) in NH₃ H₂O (60 mL) was stirred at 100° C. for 16hours. On completion, the reaction mixture was concentrated in vacuo togive the title compound (5.10 g, 98% yield) as a light yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H).

(E)-N,N-dimethyl-2-nitro-ethenamine (Intermediate CK)

A mixture of 1,1-dimethoxy-N,N-dimethyl-methanamine (20.0 g, 167 mmol,22.30 mL) in MeNO₂ (12.8 mL) was stirred at 80° C. for 30 minutes. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by column chromatography to give the title compound (14.0 g,72% yield) as a red brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13 (d,J=10.8 Hz 1H), 6.62 (d, J=10.8 Hz, 1H), 3.21 (s, 3H), 2.88 (s, 3H).

Methyl 4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate (Intermediate CL)

Step 1—Ethyl (2E)-2-[(4-bromophenyl)hydrazono]-2-chloro-acetate

To a mixture of 4-bromoaniline (50.0 g, 291 mmol) in a mixed solvent ofHCl (12 N, 72.6 mL) and H₂O (150 mL) was added a solution of NaNO₂ (22.1g, 319 mmol) in H₂O (50 mL) dropwise at −5° C. The mixture was stirredat 0° C. for 0.5 hour. Then ethyl 2-chloro-3-oxo-butanoate (50.2 g, 305mmol, 42.2 mL) and NaOAc (71.53 g, 872 mmol) were added to the solutionat 0° C. and the mixture was stirred for 30 minutes. The reactionmixture was then allowed to warm to rt and stirred for an additional for2 hours. On completion, the reaction mixture was filtered and the filtercake was dried in vacuo. The residue was triturated with MeOH (500 mL)to give the title compound (50.0 g, 56% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.45-7.20 (m, 2H), 7.14-7.11 (m, 2H),4.40 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2 Hz, 3H).

Step 2—Ethyl 1-(4-bromophenyl)-4-nitro-pyrazole-3-carboxylate

Ethyl (2Z)-2-[(4-bromophenyl)hydrazono]-2-chloro-acetate (1.00 g, 3.27mmol), (E)-N,N-dimethyl-2-nitro-ethenamine (380 mg, 3.27 mmol,Intermediate CK) and Et₃N (331 mg, 3.27 mmol) were taken up into amicrowave tube in CHCl₃ (3 mL). The sealed tube was heated at 140° C.for 1 hour under microwave. On completion, the mixture was concentratedin vacuo. The residue was purified by reverse phase flash (0.1% FA inwater) to give the title compound (350 mg, 28% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 7.97-7.90 (m, 2H), 7.85-7.78(m, 2H), 4.43 (q, J=7.2 Hz, 2H), 1.34 (t, J=7.2 Hz, 3H).

Step 3—1-(4-Bromophenyl)-4-nitro-pyrazole-3-carboxamide

To a solution of ethyl 1-(4-bromophenyl)-4-nitro-pyrazole-3-carboxylate(0.50 g, 1.47 mmol) in THF (10 mL) was added NH₃ H₂O (15.1 g, 129 mmol,16.6 mL, 30 wt %). The mixture was stirred at 110° C. for 3 hours in aseal tube. On completion, the reaction mixture was concentrated in vacuoto give the title compound (500 mg, 98% yield) as pale solid. LC-MS(ESI⁺) m/z 310.9 (M+H)⁺.

Step 4—4-Amino-1-(4-bromophenyl)pyrazole-3-carboxamide

To a solution of 1-(4-bromophenyl)-4-nitro-pyrazole-3-carboxamide (500mg, 1.61 mmol) in MeOH (10 mL) and H₂O (4 mL) was added Fe (898 mg, 16.0mmol) and NH₄Cl (860 mg, 16.0 mmol). The mixture was stirred at 75° C.for 5 hours. On completion, the mixture was filtered and the filtratewas concentrated in vacuo. The residue was dissolved in EA (30 mL) andwashed with water (10 mL). The organic layer was separated andconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (230 mg, 49% yield) as ayellow solid. LC-MS (ESI⁺) m/z 304.9 (M+Na+2)⁺.

Step 5—Methyl 4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate

A mixture of 4-amino-1-(4-bromophenyl)pyrazole-3-carboxamide (0.23 g,818 umol), dppf (18.2 mg, 32.0 umol), Pd(OAc)₂ (7.35 mg, 32.0 umol) inDMF (5 mL) and MeOH (5 mL) was degassed and purged with nitrogen gasthree times. Then the mixture was stirred at 80° C. for 16 h under COatmosphere (50 psi pressure). On completion, the mixture was filteredand the filtrate was concentrated to remove MeOH. Then the residue wasdiluted with EA (200 mL) and washed with water (2×50 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by silica gel chromatography to give thetitle compound (140 mg, 61% yield) as a light yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 8.12-7.96 (m, 4H), 7.89 (s, 1H), 7.62 (s, 1H), 7.33 (s,1H), 4.95 (s, 2H), 3.87 (s, 3H); LC-MS (ESI⁺) m/z 261.0 (M+H)⁺.

2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicAcid (Intermediate CM)

Step 1—Tert-Butyl N-(4-bromo-2-pyridyl)carbamate

A solution of 4-bromopyridin-2-amine (5.00 g, 28.9 mmol) in dry THF (100mL) was treated with LiHMDS (1 M, 57.8 mL) at −5° C. and the solutionwas stirred at −5° C. for 10 minutes. Then (Boc)₂O (6.31 g, 28.9 mmol)was added and the mixture was allowed to warm to rt and stirred for 1 h.On completion, the reaction mixture was quenched with saturated ammoniumchloride solution (20 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with brine (20 mL), dried withNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography to give the title compound (6.50 g, 82%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ −8.92 (s, 1H), 8.27(d, J=0.8 Hz, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.12 (dd, J=1.6, 5.2 Hz, 1H),1.55 (s, 9H).

Step 2—Tert-ButylN-(4-bromo-2-pyridyl)-N-(2,2,2-trifluoroethyl)carbamate

To a mixture of tert-butyl N-(4-bromo-2-pyridyl)carbamate (6.10 g, 22.3mmol), cesium carbonate (11.0 g, 33.7 mmol) and DMF (60 mL) was added2,2,2-trifluoroethyl trifluoromethanesulfonate (5.18 g, 22.3 mmol). Thereaction mixture was stirred at rt for 15 h. On completion, the reactionmixture was quenched with saturated aqueous ammonium chloride solution(50 mL) and extracted with ethyl acetate (3×100 mL). The organic layerwas washed with saturated brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography to give the title compound (5.70 g, 72%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ −8.18 (d, J=5.2 Hz,1H), 8.01-7.94 (m, 1H), 7.24 (dd, J=1.6, 5.2 Hz, 1H), 4.81 (q, J=8.8 Hz,2H), 1.55 (s, 9H).

Step 3—Tert-butylN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-(4-bromo-2-pyridyl)-N-(2,2,2-trifluoroethyl)carbamate (3.00 g, 8.45mmol) in dioxane (60 mL) was added4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(10.7 g, 42.2 mmol), KOAc (1.66 g, 16.9 mmol) and Pd(dppf)Cl₂ CH₂Cl₂(345 mg, 423 umol) under nitrogen atmosphere. The reaction mixture wasthen heated to 65° C. and stirred for 2 h. On completion, the reactionmixture was diluted with ethyl acetate (100 mL) and filtered. Thefiltrate was concentrated in vacuo. The residue was purified by silicagel column chromatography to give the title compound (3.00 g, 96% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.38 (dd, J=0.8, 4.8 Hz,1H), 7.91 (s, 1H), 7.42 (d, J=4.8 Hz, 1H), 4.76 (q, J=8.8 Hz, 2H), 1.52(s, 9H), 1.35 (s, 12H).

Step 4—Ethyl2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylate

To a solution of tert-butylN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(4.00 g, 9.94 mmol), ethyl 2-bromooxazole-4-carboxylate (2.19 g, 9.94mmol) in dioxane (40 mL) and H₂O (8 mL) was added Cs₂CO₃ (6.48 g, 19.9mmol) and Pd(dppf)Cl₂·CH₂Cl₂ (406 mg, 497 umol) and the mixture wasstirred at 80° C. for 16 h. On completion, the reaction mixture wasdiluted with ethyl acetate (200 mL) and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography to give the title compound (2.10 g, 51% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ=8.50 (d, J=5.2 Hz, 1H), 8.38 (s,1H), 8.34 (s, 1H), 7.79 (d, J=5.2 Hz, 1H), 4.85 (q, J=8.8 Hz, 2H), 4.45(q, J=7.2 Hz, 2H), 1.56 (s, 9H), 1.43 (t, J=7.2 Hz, 3H); LC-MS (ESI⁺)m/z 416.1 (M+H)⁺.

Step5—2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicAcid

To a solution of ethyl2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylate(100 mg, 241 umol) in THF (1 mL) and H₂O (200 uL) was added LiOH (11.5mg, 482 umol). The mixture was stirred at rt for 0.5 h. On completion,the reaction mixture was acidified with 1N HCl (3 mL) to pH=5, thenextracted with ethyl acetate (5×20 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give the title compound (90.0 mg, 97%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ=8.53 (dd, J=0.8, 5.2Hz, 1H), 8.46 (s, 1H), 8.40 (s, 1H), 7.79 (dd, J=1.2, 5.2 Hz, 1H),7.81-7.77 (m, 1H), 4.86 (q, J=8.8 Hz, 2H), 1.57 (s, 9H); LC-MS (ESI⁺)m/z 388.1 (M+H)⁺

4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicAcid (Intermediate CN)

Step 1—Methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate

To a mixture of methyl 4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate (120mg, 461 umol, Intermediate CL) and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (179 mg, 461, Intermediate CM) in DMF (5 mL) was added DIPEA (179mg, 1.38 mmol) and HATU (210 mg, 553 umol) and the mixture was stirredat rt for 2 h. On completion, the mixture was diluted with water (20mL), extracted with EA (2×50 mL), and the organic layer was concentratedin vacuo. The residue was purified by silica gel chromatography to givethe title compound (223 mg, 72% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.07 (s, 1H), 9.11 (s, 1H), 9.06 (s, 1H), 8.74-8.61 (m,1H), 8.26 (s, 1H), 8.16-8.05 (m, 5H), 7.86-7.75 (m, 2H), 4.91 (m, 2H),3.89 (s, 3H), 1.54 (s, 9H); LC-MS (ESI⁺) m/z 630.2 (M+H)⁺.

Step2—4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicAcid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate (210 mg, 333umol) in THF (5 mL) and H₂O (5 mL) was added LiOH (40.0 mg, 1.67 mmol).The mixture was stirred at rt for 16 h. On completion, the mixture wasadjusted to pH=6 with 1N HCl, then extracted with EA (2×100 mL). Theorganic layer was concentrated in vacuo to give the title compound (150mg, 68% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 9.12 (s, 1H), 8.99 (s, 1H), 8.67 (d, J=5.2 Hz, 1H), 8.26 (s, 1H),8.13-7.97 (m, 5H), 7.79-7.76 (m, 2H), 7.76 (s, 1H), 4.91 (m, 2H), 1.54(s, 9H); LC-MS (ESI⁺) m/z 616.2 (M+H)⁺.

5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (IntermediateCO)

To a solution of 4-bromophthalic anhydride (15.0 g, 66.1 mmol, CAS#86-90-8) in acetic acid (225 mL) was added 2,6-dioxopiperidin-3-aminehydrochloride (10.87 g, 66.1 mmol, CAS #24666-56-6) and sodium acetate(5.42 g, 66.07 mmol) at rt. The reaction mixture was heated to 80° C.and stirred for 16 h. The resulting reaction mixture was cooled to rtand concentrated on a rotary evaporator. The obtained residue wassuspended in water (255 mL) and the resulting mixture was cooled to 0°C. The resulting slurry was stirred at 0° C. for 1 h. The resultingprecipitate was filtered, washed with water (60 mL) and dried undervacuum to give the title compound (20.44 g, 92%) as a purple solid.LC-MS (ESI⁺) m/z 336.9 (M+H)⁺.

5-(3-(2-aminoethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Intermediate CP)

Step 1—Tert-butyl N-(2-prop-2-ynoxyethyl)carbamate

To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (1 g, 6.20 mmol)and 3-bromoprop-1-yne (775 mg, 6.51 mmol) in THF (30 mL) was added TBAI(137 mg, 372 umol) and KI (154 mg, 931 umol). Then KOH (409 mg, 6.20mmol) was added into the above mixture and the reaction mixture wasstirred at rt for 20 h. On completion, the mixture was concentrated invacuo to remove the solvent. The residue was diluted with water (40 mL)and extracted with EA (3×30 mL). The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (SiO₂) to give the title compound (0.84 g, 68%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.84 (s, 1H), 4.09(d, J=2.4 Hz, 2H), 3.52 (t, J=5.2 Hz, 2H), 3.28-3.26 (m, 2H), 2.38 (t,J=2.4 Hz, 1H), 1.38 (s, 9H).

Step 2—Tert-Butyl(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate

5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.4 g, 1.19mmol, Intermediate CO), CuI (22.6 mg, 119 umol) and Pd(PPh₃)₂Cl₂ (83.3mg, 119 umol) were put into a microwave tube. Then tert-butylN-(2-prop-2-ynoxyethyl)carbamate (473 mg, 2.37 mmol), TEA (2.16 g, 2.98mL, 21.4 mmol) and DMF (3 mL) were added into the tube. The mixture wasdegassed with nitrogen for 5 minutes. The sealed tube was then heated at80° C. for 30 minutes under microwave. On completion, the reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatography (SiO₂) to give thetitle compound (510 mg, 94% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 8.16 (s, 1H), 7.92 (s, 1H), 7.87-7.78 (m, 2H), 5.03-4.96 (m,1H), 4.94 (s, 1H), 4.43 (s, 2H), 3.67 (t, J=5.2 Hz, 2H), 3.39 (d, J=5.2Hz, 2H), 2.96-2.90 (m, 1H), 2.88-2.80 (m, 1H), 2.79-2.71 (m, 1H),2.21-2.13 (m, 1H), 1.45 (s, 9H).

Step 3—Tert-butyl(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propoxy)ethyl)carbamate

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethyl]carbamate (490 mg, 1.08 mmol) in THF (5 mL) was added Pd/C (0.2 g,329 umol, 10 wt %) and Pd(OH)₂/C (0.2 g, 329 umol, 10 wt %). Thereaction mixture was stirred at rt for 18 h under hydrogen atmosphere(15 Psi pressure). On completion, the mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (370 mg,75% yield) as a yellow oil. LC-MS (ESI⁺) m/z 360.0 (M+H−100)⁺.

Step4—5-(3-(2-aminoethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethyl]carbamate (120 mg, 26 umol) in DCM (1 mL) was added HC/dioxane (4 M, 1mL). The reaction mixture was stirred at rt for 0.5 hr. On completion,the mixture was concentrated in vacuo to give the title compound (90 mg,96% yield) as a yellow oil. LC-MS (ESI⁺) m/z 360.0 (M+H)⁺.

5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Intermediate CO)

Step 1—Tert-Butyl N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate

To a solution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (5.00g, 24.4 mmol, CAS #139115-91-6) and 3-bromoprop-1-yne (2.90 g, 24.4mmol, 2.10 mL) in THF (40 mL) was added TBAI (540 mg, 1.46 mmol), KI(606 mg, 3.65 mmol) and KOH (1.61 g, 24.4 mmol, 85% wt %). The reactionmixture was stirred at rt for 16 h. On completion, the mixture wasfiltered, and the filtrate was concentrated in vacuo to give a residue.The residue was diluted with H₂O (20 mL) and extracted with EA (2×50mL). The organic phase was concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether:Ethyl acetate=5:1) to give the title compound (4.00 g, 67% yield)as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.02 (s, 1H), 4.17 (d, J=2.4Hz, 2H), 3.68-3.63 (m, 2H), 3.62-3.58 (m, 2H), 3.51 (t, J=5.2 Hz, 2H),3.28 (q, J=5.2 Hz, 2H), 2.43 (t, J=2.4 Hz, 1H), 1.43 (s, 9H).

Step 2—Tert-Butyl(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

To a solution of5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (300 mg, 890umol, Intermediate CO) and tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (433 mg, 1.78 mmol) in DMF (8mL) was added Pd(PPh₃)₂Cl₂ (62.5 mg, 88.9 umol), TEA (1.62 g, 16.0 mmol,2.23 mL) and CuI (16.9 mg, 88.9 umol). The reaction mixture was heatedat 80° C. for 30 minutes under microwave. On completion, the mixture wasconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether:Ethyl acetate=5:1 to 1:0)to give the title compound (440 mg, 89% yield) as a yellow solid. LC-MS(ESI⁺) m/z 400.1 (M+H−100)⁺.

Step 3—Tert-Butyl(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propoxy)ethoxy)ethyl)carbamate

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate (580 mg, 1.16 mmol) in THF (10 mL) was added Pd/C(300 mg, 10 wt %) and Pd(OH)₂/C (300 mg, 10 wt %). The reaction mixturewas stirred at rt under hydrogen atmosphere (15 psi pressure) for 12 h.On completion, the residue was filtered and the filter was concentratedin vacuo to give the title compound (500 mg, 85% yield) as a yellow oil.LC-MS (ESI⁺) m/z 526.1 (M+Na)⁺.

Step4—5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethyl]carbamate (200 mg, 397 umol) in DCM (2 mL) was added HCl indioxane (4 M, 2.00 mL), and the reaction mixture was stirred at rt for20 minutes. On completion, the mixture was concentrated in vacuo to givethe title compound (160 mg, 99% yield) as a yellow solid. LC-MS (ESI⁺)m/z 404.0 (M+H)⁺.

2-[2-[2-[(4-Methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethanamine(Intermediate CR)

Step 1—Tert-ButylN-[2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethyl]carbamate

To a mixture of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethylmethanesulfonate (1.30 g, 3.97 mmol, synthesized via Step 1 ofIntermediate AM) and 1-(4-methoxyphenyl)-N-methyl-methanamine (600 mg,3.97 mmol) in DMF (15 mL) was added K₂CO₃ (1.10 g, 7.94 mmol). Thereaction mixture was stirred at rt for 16 hours. On completion, themixture was diluted with water (10 mL) and extracted with DCM (3×20 mL).The organic layers were dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated in vacuo to give a residue. The residue waspurified by reverse phase chromatography (0.1% NH₃ H2O) to give thetitle compound (670 mg, 44% yield) as a light yellow oil. LC-MS (ESI⁺)m/z 383.2 (M+H)⁺.

Step2—2-[2-[2-[(4-Methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethanamine

To a mixture of tert-butylN-[2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethyl]carbamate (470 mg, 1.23 mmol) in DCM (4 mL) was added HCl in dioxane (4M, 1.5 mL). The reaction mixture was stirred at rt for 2 hours. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (350 mg, 95% yield) as a light yellow oil. LC-MS (ESI⁺) m/z283.1 (M+H)⁺.

5-(1-amino-3,6,9,12-tetraoxapentadec-14-yn-15-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride (Intermediate CS)

Step 1—Tert-Butyl(15-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-yl)carbamate

In a flame dried reaction assembly equipped with nitrogen bubbler wasprepared a solution of5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.0 g, 3.0mmol, Intermediate CO) and tert-butyl(3,6,9,12-tetraoxapentadec-14-yn-1-yl)carbamate (1.18 g, 3.56 mmol,Intermediate EW) in DMF (20 mL) at rt. Cuprous iodide (0.11 g, 0.59mmol) and TEA (5.0 mL, 36.0 mmol) were sequentially added to thereaction mixture at rt. The resulting reaction mixture was degassed withargon for 10-15 min. Then Pd(PPh₃)₂Cl₂ (0.02 g, 0.029 mmol) was added tothe reaction mixture and argon purging was continued for 5-10 min. Thereaction mixture was then heated at 70° C. and stirred for 0.5 h underargon atmosphere. The resulting reaction mixture was then cooled to rtand concentrated on a rotary evaporator. The obtained crude product waspurified by gradient column chromatography using neutral alumina asstationary phase and DCM/IPA as a mobile phase. The title compound (1.1g, 63%) was isolated as a light yellow viscous oil which solidified uponstanding overnight at 0-5° C. temperature. LC-MS (ESI⁺) m/z 488.0(M−100+H)⁺.

Step2—5-(1-amino-3,6,9,12-tetraoxapentadec-14-yn-15-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride

To a solution of tert-butyl(15-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-yl)carbamate(2.1 g, 35.8 mmol) in 1,4-dioxane (5 mL) was added 4N HCl in Dioxane (20mL) at rt. The reaction mixture was stirred at rt for 5 h. The resultingreaction mixture was concentrated under vacuum to get a brown colorviscous liquid which was further triturated with diethyl ether (20 mL)followed by n-pentanes (30 mL) to give the title compound (1.9 g, 99%)as a yellowish hydroscopic solid. LC-MS (ESI⁺) m/z 488.0 (M+H)⁺.

5-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride (Intermediate CT)

Step-1 Tert-Butyl(15-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6,9,12-tetraoxapentadecyl)carbamate

To a solution of tert-butyl(15-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6,9,12-tetraoxapentadec-14-yn-1-yl)carbamate(3.0 g, 51.0 mmol, synthesized via Step 1 of Intermediate CS) in ethanol(100 mL) was added Pd/C (1.5 g, 10 wt %) under nitrogen atmosphere.Hydrogen gas was purged into the reaction mixture and the reaction wasstirred for 6 h at rt. The resulting reaction mixture was filteredthrough a pad of celite and washed with ethanol (30 mL). The resultingfiltrate was concentrated under vacuum to give the title compound (3.0g, 96%) as a green viscous oil. LC-MS (ESI⁺) m/z 492.0 (M−100+H)⁺.

Step-25-(1-amino-3,6,9,12-tetraoxapentadecan-15-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride

To a solution of tert-butyl(15-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,6,9,12-tetraoxapentadecyl)carbamate(3.0 g, 50.7 mmol) in 1,4-dioxane (20 mL) was added 4N HCl in dioxane(25 mL) at rt. The reaction mixture was stirred at rt for 5 h. Theresulting reaction mixture was concentrated under vacuum to get a browncolor viscous liquid which was further triturated with diethyl ether (30mL) followed by n-pentanes (30 mL) to give the title compound (2.5 g,93%) as a brown liquid. LC-MS (ESI⁺) m/z 492.4 (M+H)⁺.

4-[4-[[6-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]pyridine-2-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicAcid (Intermediate CU)

Step 1—Ethyl6-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]pyridine-2-carboxylate

To a mixture of ethyl 6-bromopyridine-2-carboxylate (1.50 g, 6.52 mmol)and tert-butylN-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(5.46 g, 6.52 mmol, synthesized via Steps 1-3 of Intermediate CM) in amixed solvent of dioxane (40 mL) and H₂O (8 mL) was added Cs₂CO₃ (6.37g, 19.5 mmol) and Pd(dppf)Cl₂ (238 mg, 326 umol). The reaction mixturewas stirred at 80° C. for 16 hours. On completion, the reaction mixturewas filtered and concentrated in vacuo. The residue was purified bycolumn chromatography to give the title compound (1.90 g, 68% yield) asa light yellow oil. LC-MS (ESI⁺) m/z 448.0 (M+Na)⁺.

Step2—6-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]pyridine-2-carboxylicAcid

To a mixture of methyl6-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]pyridine-2-carboxylate(800 mg, 1.94 mmol) in a mixed solvent of THF (6 mL), H₂O (1 mL) andMeOH (1 mL) was added LiOH (93.1 mg, 3.89 mmol). The reaction mixturewas stirred at rt for 0.5 hour. On completion, the reaction mixture wasacidified with HCl (1 N) until the pH=5-6 and concentrated in vacuo togive the title compound (700 mg, 95% yield) as a white solid. LC-MS(ESI⁺) m/z 420.1 (M+Na)⁺.

Step 3—Methyl4-[4-[[6-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridy]pyridine-2-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate

To a mixture of methyl 4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate (550mg, 2.11 mmol, Intermediate CL) and DIPEA (975 mg, 7.55 mmol in DMF (8mL) was added 6-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]pyridine-2-carboxylic acid (600mg, 1.51 mmol) and HATU (688 mg, 1.81 mmol). The reaction mixture wasstirred at rt for 0.5 hour. On completion, the reaction mixture wasdiluted with water (10 mL) and extracted with EA (4×10 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was purified by prep-HPLC (0.1% FA)to give the title compound (140 mg, 14% yield) as a white solid. LC-MS(ESI⁺) m/z 640.2 (M+H)⁺.

Step4—4-[4-[[6-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]pyridine-2-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicAcid

To a mixture of methyl4-[4-[[6-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]pyridine-2-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate (80.0 mg,125 umol) in a mixed solvent of THF (4 mL), MeOH (1 mL) and H₂O (1 mL)was added LiOH (14.9 mg, 625 umol). The reaction mixture was stirred atrt for 4 hours. On completion, the reaction mixture was acidified withHCl (1 N) until the pH=5-6 and concentrated in vacuo to give the titlecompound (120 mg, 100% yield) as a brown solid. LC-MS (ESI⁺) m/z 626.2(M+H)⁺.

N-[1-[4-(bromomethyl)phenyl]-3-carbamoyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(Intermediate CV)

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (1.00 g, 1.62 mmol, Intermediate CN) in THF (30 mL) was added TEA(329 mg, 3.25 mmol) and isopropyl carbonochloridate (398 mg, 3.25 mmol).The mixture was stirred at −10° C. for 2 hours, then the mixture wasfiltered and washed with THF (30 mL). To the filtrate was then addedNaBH₄ (246 mg, 6.50 mmol) and H₂O (5 mL) at 0° C. and the mixture wasstirred at 0° C. for 1 hour. On completion, the mixture was extractedwith DCM (200 mL). The organic layer was concentrated in vacuo and theresidue was triturated in DCM to give the title compound (420 mg, 43%yield) as a white solid. LC-MS (ESI⁺) m/z 602.2 (M+H)⁺.

Step2—N-[1-[4-(bromomethyl)phenyl]-3-carbamoyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(0.25 g, 416 umol) in DCM (5 mL) was added PBr₃ (169 mg, 623 umol). Thenthe reaction mixture was stirred at rt for 3 hours. On completion, thereaction mixture was quenched with water (20 mL), washed with saturatedNaHCO₃ (30 mL), and extracted with DCM (3×30 mL). The organic layer wasdried with Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (0.10 g, 34% yield) as a pale solid. LC-MS (ESI⁺) m/z 565.9(M+H)⁺.

4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylicAcid (Intermediate CW)

Step 1—Methyl 4-methylsulfonyloxycyclohexanecarboxylate

To a solution of methyl 4-hydroxycyclohexanecarboxylate (5.00 g, 31.6mmol) and TEA (6.40 g, 63.2 mmol, 8.80 mL) in DCM (50 mL) was added MsCl(4.34 g, 37.9 mmol, 2.94 mL) dropwise at 0° C. Then the reaction mixturewas allowed to warm to rt and stirred for 3 hours. On completion, themixture was diluted with H₂O (20 mL), then extracted with DCM (2×40 mL).The combined organic phase was dried over by Na₂SO₄ and concentrated invacuo to give the title compound (7.00 g, 93% yield) as a white solid.

Step 2—Methyl 4-(3-carbamoyl-4-nitro-pyrazol-1-yl)cyclohexanecarboxylate

To a solution of 4-nitro-1H-pyrazole-3-carboxamide (4.62 g, 29.6 mmol,Intermediate CJ) and methyl 4-methylsulfonyloxycyclohexanecarboxylate(7.00 g, 29.6 mmol) in DMF (100 mL) was added Cs₂CO₃ (19.3 g, 59.2mmol). The reaction mixture was stirred at 130° C. for 12 hours. Oncompletion, the mixture was filtered, and concentrated in vacuo to givea residue. The residue was purified by reverse phase chromatography(0.1% NH₃ H2O) to give the title compound (2.20 g, 25% yield) as ayellow oil. LC-MS (ESI⁺) m/z 297.2 (M+H)⁺.

Step 3—Methyl 4-(4-amino-3-carbamoyl-pyrazol-1-yl)cyclohexanecarboxylate

To a solution of methyl4-(3-carbamoyl-4-nitro-pyrazol-1-yl)cyclohexanecarboxylate (0.60 g, 2.03mmol) in MeOH (10 mL) was added Pd/C (400 mg, 10 wt %). The reactionmixture was stirred under hydrogen atmosphere (15 psi pressure) at rtfor 16 hours. On completion, the mixture was filtered and the filtratewas concentrated in vacuo to give the title compound (490 mg, 90% yield)as a purple oil. LC-MS (ESI⁺) m/z 267.1 (M+H)⁺.

Step 4—methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylate

To a solution of methyl4-(4-amino-3-carbamoyl-pyrazol-1-yl)cyclohexanecarboxylate (150 mg, 563umol) and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (218 mg, 563 umol, Intermediate CM) in DMF (5 mL) was added DIPEA(363 mg, 2.82 mmol, 490 uL). The mixture was stirred at rt for 12minutes, then HATU (257 mg, 675 umol) was added and the reaction mixturewas stirred at rt for 12 hours. On completion, the mixture was dilutedwith H₂O (10 mL) and then extracted with EtOAc (2×20 mL). The organicphase was dried over Na₂SO₄, filtrated and concentrated in vacuo to givethe title compound (400 mg, 83% purity, 92% yield) as a white solid.LC-MS (ESI⁺) m/z 636.2 (M+H)⁺.

Step5—4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylicAcid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]cyclohexanecarboxylate(400 mg, 629 umol) in THF (10 mL) and H₂O (2 mL) was added LiOH (22.6mg, 944 umol). The reaction mixture was stirred at rt for 12 hours. Oncompletion, the mixture was concentrated in vacuo to remove THF, thendiluted with H₂O (20 mL). The mixture was adjusted to pH=5 with 1N HCl,then extracted with EA (2×40 mL). The combined organic phase was driedwith Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (330 mg, 84%) as a yellow solid. LC-MS (ESI⁺) m/z 644.2(M+Na)⁺.

N-[3-carbamoyl-1-(4-piperidyl)pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(Intermediate CX)

Step 1—Tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate

To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g,24.8 mmol) and TEA (5.03 g, 49.6 mmol) in DCM (50 mL) was added MsCl(4.27 g, 37.2 mmol). The reaction mixture was stirred at rt for 0.5hour. On completion, the reaction mixture was diluted with water (10 mL)and acidified with citric acid solution until the pH=5-6. Then themixture was extracted with DCM (3×15 mL). The combined organic layerswere diluted with water (10 mL) and basified with NaHCO₃ solution untilthe pH=7-8. Then the mixture was extracted with DCM (3×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (7.00 g, 90% yield) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.84 m 4.78 (m, 1H), 3.68-3.59(m, 2H), 3.26-3.20 (m, 2H), 2.97 (s, 3H), 1.94-1.84 (m, 2H), 1.80-1.69(m, 2H), 1.39 (s, 9H).

Step 2—Tert-Butyl4-(3-carbamoyl-4-nitro-pyrazol-1-yl)piperidine-1-carboxylate

To a mixture of 4-nitro-1H-pyrazole-3-carboxamide (3.91 g, 25.0 mmol,Intermediate CJ) and tert-butyl4-methylsulfonyloxypiperidine-1-carboxylate (7.00 g, 25.0 mmol) in DMF(70 mL) was added Cs₂CO₃ (16.3 g, 50.1 mmol). The reaction mixture wasstirred at 130° C. for 16 hours. On completion, the reaction mixture wasconcentrated in vacuo. The residue was purified by prep-HPLC (0.1% NH₃H₂O) to give the title compound (1.80 g, 21% yield) as a brown solid. ¹HNMR (400 MHz, DMSO-d₆) δ=8.95 (s, 1H), 8.00 (s, 1H), 7.76 (s, 1H),4.49-4.43 (m, 1H), 4.06 (d, J=11.6 Hz, 2H), 3.01-2.70 (m, 2H), 2.04 (d,J=9.6 Hz, 2H), 1.87-1.70 (m, 2H), 1.42 (s, 9H).

Step 3—Tert-Butyl4-(4-amino-3-carbamoyl-pyrazol-1-yl)piperidine-1-carboxylate

To a mixture of tert-butyl4-(3-carbamoyl-4-nitro-pyrazol-1-yl)piperidine-1-carboxylate (1.80 g,5.30 mmol) in MeOH (30 mL) was added Pd/C (1.00 g, 10 wt %) underhydrogen atmosphere (15 psi pressure). The reaction mixture was stirredat rt for 16 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound (610 mg, 100% yield) asa light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.17 (s, 1H), 7.08 (s,1H), 6.98 (s, 1H), 4.70-4.53 (m, 2H), 4.25-4.17 (m, 1H), 4.03 (d, J=11.2Hz, 2H), 2.99-2.80 (m, 2H), 1.94 (d, J=10.0 Hz, 2H), 1.80-1.70 (m, 2H),1.42 (s, 9H).

Step4—Tert-butyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]piperidine-1-carboxylate

To a mixture of tert-butyl4-(4-amino-3-carbamoyl-pyrazol-1-yl)piperidine-1-carboxylate (159 mg,516 umol) and DIPEA (200 mg, 1.55 mmol) in DMF (5 mL) was added2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylic acid (200mg, 516 umol, Intermediate CM) and HATU (235 mg, 619 umol). The reactionmixture was stirred at rt for 0.5 hour. On completion, the reactionmixture was diluted with water (10 mL) and extracted with EA (3×10 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (400 mg, 80% purity,91% yield) as a light yellow solid. LC-MS (ESI⁺) m/z 679.3 (M+H)⁺.

Step5—N-[3-carbamoyl-1-(4-piperidyl)pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture of tert-butyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]piperidine-1-carboxylate(400 mg, 589 umol) in DCM (4 mL) was added HCl in dioxane (4 M, 2 mL).The reaction mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(280 mg, HCl salt) as a light yellow solid. LC-MS (ESI⁺) m/z 479.2(M+H)⁺.

Tert-Butyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetate (IntermediateCY)

Step 1—2-(2-(2-Hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

To a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (50.0 g, 333 mmol,44.6 mL) in DCM (1 L) was added Ag₂O (84.9 g, 366 mmol) and KI (5.53 g,33.3 mmol) and TsCl (63.5 g, 333 mmol). The reaction mixture was stirredat rt for 18 hours. On completion, the reaction mixture was filtered andthe filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography to give the title compound (76.0 g, 74% yield)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=8.0 Hz, 2H),7.35 (d, J=8.0 Hz, 2H), 4.20-4.15 (m, 2H), 3.74-3.69 (m, 4H), 3.64-3.56(m, 6H), 2.45 (s, 3H); LC-MS (ESI⁺) m/z 305.0 (M+H)⁺.

Step 2—2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethyl)isoindoline-1,3-dione

To a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethyl4-methylbenzenesulfonate (20.0 g, 65.7 mmol) in DMF (200 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (12.8 g, 69.0 mmol). The resultingreaction mixture was stirred at 80° C. for 12 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography to give the title compound (14.6 g, 80% yield)as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.83 (m, 2H),7.75-7.69 (m, 2H), 3.95-3.90 (m, 2H), 3.79-3.74 (m, 2H), 3.69-3.64 (m,4H), 3.63-3.59 (m, 2H), 3.56-3.52 (m, 2H).

Step 3—Tert-Butyl2-(2-(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethoxy)ethoxy)acetate

To a solution of2-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]isoindoline-1,3-dione (10.0 g,35.8 mmol) and Rh(OAc)₂ (396 mg, 1.79 mmol) in DCM (50 mL) was added asolution of tert-butyl 2-diazoacetate (7.63 g, 53.7 mmol) in DCM (200mL) dropwise. The reaction mixture was stirred at rt for 18 hours. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by silica gel chromatography to give the title compound(11.0 g, 78% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.88-7.82 (m, 2H), 7.75-7.69 (m, 2H), 3.99 (s, 2H), 3.94-3.88 (m, 2H),3.77-3.72 (m, 2H), 3.68-3.58 (m, 8H), 1.47 (s, 9H).

Step 4—Tert-Butyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)acetate

To a solution of tert-butyl2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]acetate (11.0g, 28.0 mmol) in ethanol (200 mL) was added NH₂NH₂—H₂O (7.00 g, 140mmol). The reaction mixture was stirred at 80° C. for 2 hours. Oncompletion, the reaction mixture was filtered. The filtrate wasconcentrated in vacuo. The residue was diluted with DCM (200 mL) andfiltered. The filtrate was concentrated in vacuo to give the titlecompound (6.40 g, 87% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 4.02 (s, 2H), 3.72-3.63 (m, 10H), 3.53-3.50 (m, 2H), 1.47 (s, 9H);LC-MS (ESI⁺) m/z 264.0 (M+H)⁺.

Ethyl 2-[2-(2-aminoethoxy)ethoxy]acetate (Intermediate CZ)

Step 1—Ethyl 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]acetate

To a mixture of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (10.0g, 48.7 mmol, CAS #139115-91-6) and Rh(OAc)₂ (215 mg, 974 umol) in DCM(150 mL) was added a solution of ethyl 2-diazoacetate (16.6 g, 146 mmol)in DCM (100 mL) dropwise. The reaction mixture was stirred at rt for 20hours. On completion, the reaction mixture was diluted with water (50mL) and extracted with DCM (2×100 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by column chromatography to give the titlecompound (12.0 g, 84% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 4.23-4.16 (m, 4H), 4.11 (s, 1H), 4.05-3.97 (m, 2H), 3.67-3.58 (m, 3H),3.51-3.41 (m, 2H), 1.47-1.37 (m, 9H), 1.28-1.26 (m, 3H).

Step 2—Ethyl 2-[2-(2-aminoethoxy)ethoxy]acetate

To a mixture of ethyl2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]acetate (3.00 g, 10.3mmol) in DCM (20 mL) was added HCl in dioxane (4 M, 10 mL). The reactionmixture was stirred at rt for 2 hours. On completion, the reactionmixture was concentrated in vacuo to give the title compound (2.00 g,100% yield) as a red brown oil. ¹H NMR (400 MHz, CDCl₃) δ 4.27-4.14 (m,3H), 4.12 (s, 1H), 4.07-3.93 (m, 2H), 3.75-3.69 (m, 3H), 3.67 (s, 2H),3.45-3.36 (m, 1H), 1.29 (t, J=7.6 Hz, 3H).

Tert-Butyl 2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetate(Intermediate DA)

Step1—2-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethyl]isoindoline-1,3-dione

To a solution of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl4-methylbenzenesulfonate (20.0 g, 57.4 mmol, synthesized via Step 1 ofIntermediate AO) in DMF (200 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (12.7 g, 68.8 mmol) and the mixturewas stirred at 80° C. for 2 h. On completion, the mixture wasconcentrated in vacuo. The residue was then diluted with EA (200 mL) andstirred for 30 min, filtered, and the organic layer was concentrated invacuo. The mixture was purified by silica gel chromatography (petroleumether:ethyl acetate=1:2) to give the title compound (9.00 g, 48% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.90-7.84 (m, 2H),7.78-7.70 (m, 2H), 3.97-3.89 (m, 2H), 3.81-3.74 (m, 2H), 3.73-3.69 (m,2H), 3.69-3.65 (m, 2H), 3.65-3.61 (m, 6H), 3.61-3.57 (m, 2H).

Step 2—Tert-Butyl2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]isoindoline-1,3-dione(1.00 g, 3.09 mmol) and Rh(OAc)₂ (27.3 mg, 123 umol) in DCM (10.0 mL)was added a solution of tert-butyl 2-diazoacetate (1.32 g, 9.28 mmol) inDCM (20 mL) dropwise at rt for 1 hr. The reaction mixture was stirred atrt for 20 h. On completion, the mixture was extracted with H₂O (3×30mL), the organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The mixture was purified by silica gelchromatography (petroleum ether:ethyl acetate=3:1) to give the titlecompound (1.00 g, 73% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl3) δ7.81-7.76 (m, 2H), 7.68-7.63 (m, 2H), 3.95 (s, 2H), 3.87-3.82 (m, 2H),3.70-3.66 (m, 2H), 3.66-3.61 (m, 2H), 3.61-3.57 (m, 4H), 3.56-3.52 (m,6H), 1.42 (s, 9H).

Step 3—Tert-Butyl 2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetate

To a solution of tert-butyl2-[2-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethoxy]ethoxy]ethoxy]acetate(1.00 g, 2.29 mmol) in EtOH (15.0 mL) was added NH₂NH₂ H₂O (233 mg, 4.57mmol, 226 uL, 98% purity), and the mixture was stirred at 80° C. for 12h. On completion, the mixture was concentrated in vacuo. The residue wasdiluted with DCM (30 mL), filtered and the organic layer wasconcentrated in vacuo to give the title compound (700 mg, 99% yield) asa yellow oil. ¹H NMR (400 MHz, CDCl3) δ 4.04 (s, 2H), 3.75-3.64 (m,12H), 3.57-3.51 (m, 2H), 2.94-2.84 (m, 2H), 2.08-1.95 (m, 2H), 1.52-1.45(m, 9H).

N-[1-(azetidin-3-yl)-3-carbamoyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(Intermediate DB)

Step 1—Tert-Butyl 3-methylsulfonyloxyazetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g,57.7 mmol) and TEA (17.5 g, 24.1 mL, 173 mmol) in DCM (80.0 mL) wasadded MsCl (9.92 g, 86.6 mmol) at 0° C. The mixture was then allowed towarm to rt and stirred for 30 min. On completion, the mixture was washedwith H₂O (3×50 mL). The organic layer was washed with brine (3×30 mL),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (14.2 g, 97% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 5.25-5.17 (m, 1H), 4.33-4.25 (m, 2H), 4.15-4.09 (m, 2H), 3.08(s, 3H), 1.46 (s, 9H).

Step 2—Tert-Butyl3-(3-carbamoyl-4-nitro-pyrazol-1-yl)azetidine-1-carboxylate

To a solution of tert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate(8.85 g, 35.2 mmol) and 4-nitro-1H-pyrazole-3-carboxamide (5.00 g, 32.0mmol, Intermediate CJ) in DMF (110 mL) was added Cs₂CO₃ (20.8 g, 64.0mmol), and the mixture was stirred at 130° C. for 16 h. On completion,the mixture was filtered and the filtrate was concentrated in vacuo. Themixture was purified by reverse phase chromatography (0.1% FA) to givethe title compound (3.50 g, 35% yield) as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 9.04 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 5.36-5.22 (m,1H), 4.38-4.27 (m, 2H), 4.22-4.08 (m, 2H), 1.41 (s, 9H).

Step 3—Tert-Butyl3-(4-amino-3-carbamoyl-pyrazol-1-yl)azetidine-1-carboxylate

To a solution of tert-butyl3-(3-carbamoyl-4-nitro-pyrazol-1-yl)azetidine-1-carboxylate (500 mg,1.61 mmol) in MeOH (5.00 mL) was added Pd/C (50.0 mg, 10 wt %) undernitrogen. The suspension was degassed under vacuum and purged withhydrogen gas several times. The mixture was stirred under hydrogenatmosphere (15 psi pressure) at rt for 14 hours. On completion, themixture was concentrated in vacuo to give the title compound (335 mg,74% yield) as a purple oil. LC-MS (ESI⁺) m/z 304.0 (M+Na)⁺

Step 4—Tert-Butyl3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoylpyrazol-1-yl]azetidine-1-carboxylate

To a solution of tert-butyl3-(4-amino-3-carbamoyl-pyrazol-1-yl)azetidine-1-carboxylate (145 mg, 516umol),2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (200 mg, 516 umol, Intermediate CM) in DMF (3.00 mL) was added HATU(235 mg, 619 umol) and DIPEA (333 mg, 2.58 mmol, 449 uL), and themixture was stirred at rt for 30 min. On completion, the mixture wasdiluted with H2O (20 mL) and stirred for 20 min. The mixture wasfiltered and the solid was dried in vacuo to give the title compound(250 mg, 74% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01(s, 1H), 9.07 (s, 1H), 8.66 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 8.25 (s,1H), 7.83 (s, 1H), 7.77 (d, J=5.2 Hz, 1H), 7.59 (s, 1H), 5.42-5.32 (m,1H), 4.96-4.87 (m, 2H), 4.36-4.28 (m, 2H), 4.27-4.17 (m, 2H), 1.53 (s,9H), 1.43 (s, 9H)

Step5—N-[1-(azetidin-3-yl)-3-carbamoyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butyl3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]azetidine-1-carboxylate(220 mg, 338 umol) in DCM (5.00 mL) was added TFA (7.70 g, 67.5 mmol),and the mixture was stirred at rt for 30 min. On completion, the mixturewas concentrated in vacuo to give the title compound (190 mg, 99% yield,TFA salt) as a white solid. LC-MS (ESI⁺) m/z 451.2 (M+H)⁺.

2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethanol (Intermediate DC)

To a solution of tert-butylN-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (2.00 g, 6.82mmol, synthesized via Steps 1-3 of Intermediate AO) in DCM (30 mL) wasadded HCl in dioxane (4 M, 10.2 mL), and the mixture was stirred rt for1 hour. On completion, the reaction mixture was concentrated in vacuo togive the title compound (1.30 g, 82% yield, HCl salt) as a brown oil. ¹HNMR (400 MHz, DMSO-d₆) δ 8.03 (s, 2H), 3.57-3.50 (m, 13H), 3.43-3.41 (m,2H), 2.97-2.90 (m, 2H).

3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicAcid (Intermediate DD)

Step 1—Ethyl (2Z)-2-[(3-bromophenyl)hydrazono]-2-chloro-acetate

To a mixture of 3-bromoaniline (30.0 g, 174 mmol) in a mixed solvent ofHCl (12 M, 43.6 mL) and H₂O (30.0 mL) was added a solution of NaNO₂(13.2 g, 191 mmol) in H₂O (10 mL) at −5° C. dropwise. Then the mixturewas stirred at 0° C. for 0.5 hr. Ethyl 2-chloro-3-oxo-butanoate (30.1 g,183 mmol) and NaOAc (42.9 g, 523 mmol) were added to the solution andthe mixture was stirred for 30 min. The reaction mixture was thenallowed to warm to rt and stirred for an additional for 2 h. Oncompletion, the mixture was filtered and the filter cake was dried invacuo to give the title compound (46.6 g, 87% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.68 (s, 1H), 7.53 (t, J=2.0 Hz, 1H),7.38-7.33 (m, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.19-7.14 (m, 1H), 4.30 (q,J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).

Step 2—Ethyl 1-(3-bromophenyl)-4-nitro-pyrazole-3-carboxylate

Ethyl (2Z)-2-[(3-bromophenyl)hydrazono]-2-chloro-acetate (2.50 g, 8.18mmol), (E)-N,N-dimethyl-2-nitro-ethenamine (950 mg, 8.18 mmol) and TEA(827 mg, 8.18 mmol) were taken up into a microwave tube in CHCl₃ (20mL). The sealed tube was heated at 140° C. for 30 min under microwave.On completion, the mixture was concentrated in vacuo. The mixture waspurified by silica column chromatography (PE:EA=10:1) to give the titlecompound (0.42 g, 15% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 8.63 (s, 1H), 7.98 (t, J=2.0 Hz, 1H), 7.71-7.66 (m, 1H), 7.64-7.61 (m,1H), 7.46-7.40 (m, 1H), 4.54 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H).

Step 3—1-(3-bromophenyl)-4-nitro-pyrazole-3-carboxamide

To a solution of ethyl 1-(3-bromophenyl)-4-nitro-pyrazole-3-carboxylate(3.00 g, 8.82 mmol) in THF (20.0 mL) was added NH₃ H₂O (13.4 g, 115mmol, 14.7 mL, 30 wt %), and the mixture was stirred at 110° C. for 16h. On completion, the mixture was concentrated in vacuo to give thetitle compound (2.70 g, 90% yield) as a yellow solid. LC-MS (ESI⁺) m/z312.9 (M+H)⁺.

Step 4—4-amino-1-(3-bromophenyl)pyrazole-3-carboxamide

To a solution of 1-(3-bromophenyl)-4-nitro-pyrazole-3-carboxamide (2.70g, 8.68 mmol) in MeOH (50.0 mL) and H₂O (25.0 mL) was added Fe (4.85 g,86.7 mmol) and NH₄Cl (4.64 g, 86.7 mmol). The mixture was stirred at 80°C. for 3 h. On completion, the mixture was filtered and the filtratedwas concentrated in vacuo to remove MeOH. The residue was extracted withEA (2×200 ml). The combined organic layer was then washed with water(200 ml) and concentrated in vacuo to give the title compound (1.90 g,77% yield) as a yellow solid. LC-MS (ESI⁺) m/z 281.0 and 283.0 (M+H)⁺.

Step 5—Methyl 3-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate

To a solution of 4-amino-1-(3-bromophenyl)pyrazole-3-carboxamide (1.90g, 6.76 mmol) in DMF (20 mL) and MeOH (20 mL) was added TEA (683 mg,6.76 mmol) and Pd(dppf)Cl₂ (494 mg, 675 umol). The mixture was stirredat 80° C. for 16 h under CO atmosphere (50 psi pressure). On completion,the mixture was concentrated in vacuo. The mixture was purified bysilica gel column chromatography (PE:EA=1:1) to give the title compound(1.10 g, 62% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.38(t, J=2.0 Hz, 1H), 8.12-8.06 (m, 1H), 7.89 (s, 1H), 7.88-7.84 (m, 1H),7.67-7.58 (m, 2H), 7.28 (s, 1H), 4.91 (s, 2H), 3.90 (s, 3H).

Step 6—Methyl3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate

To a solution of methyl 3-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate(300 mg, 1.15 mmol),2-[2-[tertbutoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (446 mg, 1.15 mmol, Intermediate CM) in DMF (5.00 mL) was addedHATU (525 mg, 1.38 mmol) and DIPEA (446 mg, 3.46 mmol), and the mixturewas stirred at 25° C. for 30 min. On completion, the mixture was dilutedwith H₂O (40 mL) and stirred for 30 min. The mixture was then filteredand the solid was dried in vacuo to give the title compound (660 mg, 90%yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H),9.11 (s, 1H), 9.04 (s, 1H), 8.67 (d, J=5.2 Hz, 1H), 8.50 (s, 1H),8.31-8.25 (m, 2H), 8.18 (s, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.81-7.75 (m,2H), 7.75-7.69 (m, 1H), 4.95-4.87 (m, 2H), 3.93 (s, 3H), 1.54 (s, 9H).

Step7—3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoic Acid

To methyl3-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate(660 mg, 1.05 mmol) in a solution of THF (10.0 mL), H2O (1.00 mL) andMeOH (1.00 mL) was added LiOH (125 mg, 5.24 mmol), and the mixture wasstirred at rt for 7 h. On completion, the mixture was diluted with H2O(50 mL) and then acidified with 1N HCl solution until the pH=5. Themixture was then extracted with EA (3×40 mL). The combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound (620 mg, 96% yield) as an off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.33 (s, 1H), 11.10 (s, 1H), 9.11(s, 1H), 9.02 (s, 1H), 8.66 (d, J=5.2 Hz, 1H), 8.49 (s, 1H), 8.27-8.21(m, 2H), 8.17 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.80-7.74 (m, 2H),7.71-7.65 (m, 1H), 4.95-4.85 (m, 2H), 1.53 (s, 9H).

4-(4-(2-(2-((Tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoicAcid (Intermediate DE)

Step 1—4-Nitro-3-(trifluoromethyl)-1H-pyrazole

To a solution of 3-(trifluoromethyl)-1H-pyrazole (5.0 g, 36.7 mmol) inconcentrated sulfuric acid (75 mL) was carefully added dropwise at 0° C.65% HNO₃ (8.91 g, 91.86 mmol, 6.36 mL). After stirring for 10 min thereaction mixture was heated to 115° C., and stirring was continued at115° C. for 4 h. On completion, the reaction mixture was cooled to rt.Then, the reaction mixture was poured onto the 200 mL ice, and extractedwith ethyl acetate (3×150 mL). The combined organic layers were washedwith brine (2×100 mL), dried over with anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (PE:EA=10:1) to give the title compound (5.9 g, 89%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.72 (s, 1H), 9.15(s, 1H).

Step 2—Methyl 4-(4-nitro-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

A mixture of 4-nitro-3-(trifluoromethyl)-1H-pyrazole (5.70 g, 31.5mmol), (4-methoxycarbonylphenyl) boronic acid (7.00 g, 38.9 mmol),pyridine (9.96 g, 125.9 mmol) and Cu(OAc)₂ (8.58 g, 47.2 mmol) in DCM(150 mL) was stirred at rt for 5 h. On completion, the reaction mixturewas concentrated in vacuo. The residue was purified by silica gelchromatography (PE:EA=10:1) to give the title compound (4.5 g, 45%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (d, J=0.6 Hz,1H), 8.22-8.12 (m, 2H), 7.82-7.74 (m, 2H), 3.90 (s, 3H).

Step 3—Methyl 4-(4-amino-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

To a solution of methyl4-[4-nitro-3-(trifluoromethyl)pyrazol-1-yl]benzoate (500 mg, 1.59 mmol)in a mixed solvent of DCM (20 mL) and MeOH (20 mL) was added Pd/C (100mg, 10 wt %) under nitrogen. The suspension was degassed under vacuumand purged with hydrogen gas several times. The mixture was stirredunder hydrogen atmosphere (15 psi pressure) at rt for 14 hours. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (450 mg, 97% yield) asa white solid. LC-MS (ESI⁺) m/z 286.0 (M+H)⁺.

Step 4—Methyl4-(4-(2-(2-((tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4—carboxamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

To a solution of methyl4-[4-amino-3-(trifluoromethyl)pyrazol-1-yl]benzoate (150 mg, 526 umol)and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (204 mg, 526 umol, Intermediate CM) in DMF (5 mL) was added HATU(240 mg, 631 umol) and DIPEA (136 mg, 1.05 mmol, 183 uL). The mixturewas stirred at rt for 1 hr. On completion, the reaction mixture wasquenched with water 50 mL. A white precipitate formed which wasfiltered. The filter cake was dried over in vacuo to give the titlecompound (300 mg, 88% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ9.07 (s, 1H), 8.98 (s, 1H), 8.55 (d, J=4.8 Hz, 1H), 8.45 (s, 1H), 8.37(s, 1H), 8.19 (d, J=8.0 Hz, 2H), 7.87 (d, J=8.0 Hz, 2H), 7.73 (d, J=4.0Hz, 1H), 4.98-4.81 (m, 2H), 3.97 (s, 3H).

Step5—4-(4-(2-(2-((Tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoicAcid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(trifluoromethyl)pyrazol-1-yl]benzoate(300 mg, 458 umol) in THF (6 mL) and H2O (2 mL) was added LiOH·HO₂ (38.5mg, 917 umol). The mixture was stirred at rt for 12 h. On completion,the reaction mixture was concentrated in vacuo to remove THF. Theresidue was acidified with 1N HCl until the pH=4, then filtered. Thefilter cake was collected to give the title compound (460 mg, 99% yield)as a white solid. LC-MS (ESI⁺) m/z 641.0 (M+H)⁺.

4-[4-[[2-[2-[Tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicAcid (Intermediate DF)

Step 1—Tert-Butyl N-(4-bromo-2-pyridyl)-N-(cyclopropylmethyl)carbamate

To a solution of tert-butyl N-(4-bromo-2-pyridyl)carbamate (5.0 g, 18.3mmol, synthesized via Step 1 of Intermediate CM) in DMF (50 mL) wasadded NaH (1.10 g, 27.5 mmol) at 0° C. for 30 minutes. Thenbromomethylcyclopropane (2.97 g, 22.0 mmol) was added into the mixture.The reaction mixture was stirred at rt for 17 h. On completion, themixture was quenched with water (40 mL) and extracted with EA (2×50 mL).The organic phase was washed with brine (60 mL), dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (2.7 g, 45% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=5.2 Hz, 1H), 7.98 (d, J=1.6Hz, 1H), 7.17 (dd, J=1.6, 5.2 Hz, 1H), 3.88 (d, J=7.2 Hz, 2H), 1.55 (s,9H), 1.22-1.15 (m, 1H), 0.47-0.40 (m, 2H), 0.28-0.23 (m, 2H).

Step 2—Ethyl2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylate

To a solution of ethyl oxazole-4-carboxylate (1.16 g, 8.25 mmol) andtert-butyl N-(4-bromo-2-pyridyl)-N-(cyclopropylmethyl)carbamate (2.7 g,8.25 mmol) in DMF (30 mL) was added tris-o-tolylphosphane (502 mg, 1.65mmol), Pd(OAc)₂ (185 mg, 825 umol) and Cs₂CO₃ (5.38 g, 16.5 mmol). Thereaction mixture was stirred at 80° C. under nitrogen for 17 h. Oncompletion, the mixture was diluted with water (50 mL) and extractedwith EA (3×50 mL). The organic layer was washed with water (100 ml),dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby silica gel chromatography to give the title compound (1.8 g, 56%yield) as a white oil. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd, J=1.6, 5.2Hz, 1H), 8.38 (s, 1H), 8.35 (s, 1H), 7.71 (dd, J=1.6, 5.2 Hz, 1H), 4.46(q, J=7.2 Hz, 2H), 3.93 (d, J=7.2 Hz, 2H), 1.57 (s, 9H), 1.44 (t, J=7.2Hz, 3H), 1.24-1.16 (m, 1H), 0.46-0.40 (m, 2H), 0.28-0.24 (m, 2H).

Step3—2-[2-Tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicAcid

To a solution of ethyl2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylate(0.5 g, 1.29 mmol) in a mixed solvent of THF (5 mL) and H₂O (1 mL) wasadded LiOH (92.7 mg, 3.87 mmol). The reaction mixture was stirred at rtfor 2 h. On completion, the mixture was acidified with 1N HCl solutionuntil the pH=3-5, then extracted with EA (2×30 mL). The combined organicphase was dried over Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (460 mg, 99% yield) as a white solid. LC-MS (ESI⁺)m/z 304.0 (M−56)⁺.

Step 4—Methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate

To a solution of2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (360 mg, 1.00 mmol) and methyl4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate (443 mg, 1.70 mmol,Intermediate CL) in DMF (5 mL) was added DIPEA (647 mg, 5.01 mmol) andHATU (457 mg, 1.20 mmol). The reaction mixture was stirred at rt for 0.5hr. On completion, the mixture was diluted with water (40 mL) andextracted with EA (2×30 mL). The combined organic layer was washed withbrine (40 mL) and concentrated in vacuo. The residue was purified bysilica gel chromatography to give the title compound (190 mg, 32% yield)as a white solid. LC-MS (ESI⁺) m/z 602.3 (M+H)⁺.

Step5—4-[4-[[2-[2-[Tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoic Acid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoate(190 mg, 316 umol) in a mixed solvent of THF (3 mL), MeOH (2 mL) and H₂O(1 mL) was added LiOH (37.8 mg, 1.58 mmol). The reaction mixture wasstirred at rt for 17 h. On completion, the mixture was acidified with 1NHCl solution until the pH=5-7, concentrated in vacuo to give the titlecompound (180 mg, 97% yield) as a yellow solid. LC-MS (ESI⁺) m/z 588.3(M+H)⁺.

4-[(1,3-Dioxoisoindolin-2-yl)methyl]benzenesulfonyl Chloride(Intermediate DG)

A mixture of 2-benzylisoindoline-1,3-dione (5.00 g, 21.0 mmol) andsulfurochloridic acid (17.1 g, 147 mmol, 9.82 mL) was stirred at 60° C.for 1.5 h until the evolution of hydrochloric gas ceased. On completion,the mixture was poured in a mixture of water and ice (100 mL), and afine white precipitate was formed. The precipitate was filtered andwashed with cold water. The precipitate was purified by columnchromatography (dichloromethane:petroleum ether=1:1) to give the titlecompound (5.20 g, 73% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.91-7.85 (m, 4H), 7.57-7.55 (m, 2H), 7.30-7.25 (m, 2H), 4.77 (s, 2H).

4-(Aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzenesulfonamide(Intermediate DH)

Step 1—7-Bromo-4-methyl-1H-indole

To a solution of 1-bromo-4-methyl-2-nitro-benzene (40.0 g, 185 mmol,25.3 mL) in tetrahydrofuran (400 mL) was added bromo(vinyl)magnesium (1M, 611 mL) at −60° C. under nitrogen gas atmosphere. The reactionmixture was then stirred at −30° C. for 1 hour. On completion, thereaction mixture was quenched with saturated ammonium chloride solution(150 mL), followed with water (100 mL). The mixture was concentrated invacuo to remove the tetrahydrofuran. The residue was extracted withethyl acetate (2×500 mL). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue was thenpurified by column chromatography (petroleum ether:ethyl acetate=100:1)to give the title compound (18.0 g, 42% yield) as a yellow oil. ¹H NMR(400 MHz, DMSO-d₆) δ 11.27 (br s, 1H), 7.37 (t, J=2.8 Hz, 1H), 7.18 (d,J=7.6 Hz, 1H), 6.75 (dd, J=0.8, 7.6 Hz, 1H), 6.57 (dd, J=1.6, 3.2 Hz,1H), 2.44 (s, 3H).

Step 2—4-Methyl-1H-indole-7-carboxylic Acid

To a mixture of potassium hydride (4.47 g, 34.27 mmol, 30 wt %)suspended in anhydrous tetrahydrofuran (80 mL) was added7-bromo-4-methyl-1H-indole (6.00 g, 28.56 mmol) dissolved intetrahydrofuran (30 mL) at 0° C. After 15 minutes, the mixture wascooled to −70° C. and t-BuLi (1.3 M, 54.9 mL) was added dropwise,keeping the temperature below −65° C. After further 15 minutes, carbondioxide gas (15 psi pressure) was bubbled into the reaction and thereaction was slowly warmed to rt over 30 minutes. On completion, thereaction mixture was quenched with ice water (120 mL), and washed withethyl acetate (3×60 mL). The aqueous phase was collected and acidifiedwith 1 N hydrochloride acid solution until the pH<7. Then, the mixturewas extracted with ethyl acetate (3×60 mL). The organic phase wascollected, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the crude product as a brown solid. Thecrude product was triturated with petroleum ether:dichloromethane (10:1,100 mL) to give the product (3.50 g, 69% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 12.82 (br s, 1H), 11.02 (br s, 1H), 7.67 (d, J=7.6Hz, 1H), 7.35 (t, J=2.8 Hz, 1H), 6.92 (d, J=7.6 Hz, 1H), 6.56 (dd,J=2.0, 3.2 Hz, 1H), 2.54 (s, 3H).

Step 3—Tert-butyl N-(4-methyl-1H-indol-7-yl)carbamate

To a solution of 4-methyl-1H-indole-7-carboxylic acid (2.20 g, 12.5mmol) in t-BuOH (36 mL) was added triethylamine (3.81 g, 37.6 mmol, 5.24mL) and DPPA (4.49 g, 16.3 mmol, 3.54 mL). The mixture was stirred at80° C. for 3 h. On completion, the reaction mixture was poured into icewater (150 mL) and extracted with ethyl acetate (3×80 mL). The organicphase was collected, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to get a residue. The residue was purified bycolumn chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) togive the title compound (2.00 g, 64% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 9.80 (br s, 1H), 7.14 (t, J=2.8 Hz, 1H), 6.70 (d,J=7.6 Hz, 1H), 6.60 (br s, 1H), 6.52 (br s, 1H), 6.45 (dd, J=2.0, 2.8Hz, 1H), 2.44 (s, 3H), 1.48 (s, 9H).

Step 4—Tert-Butyl N-(3-formyl-4-methyl-1H-indol-7-yl)carbamate

Phosphorus oxychloride (2.61 g, 17.0 mmol, 1.58 mL) was added toanhydrous N,N-dimethyl-formamide (20 mL) at 0° C. under nitrogenatmosphere and the reaction mixture was stirred for 30 minutes.Tert-butyl N-(4-methyl-1H-indol-7-yl)carbamate (2.80 g, 11.3 mmol)dissolved in N,N-dimethylformamide (8 mL) was then added dropwise andthe reaction mixture was allowed to warm to rt and then stirred for 1.5hrs. Next, to the reaction mixture was added 30% sodium hydroxide (100mL) and the mixture was heated to reflux for 30 minutes. On completion,the mixture was extracted with ethyl acetate (3×150 mL). The organicphase was collected, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (Petroleum ether:Ethyl acetate=3:1 to 0:1) to givethe title compound (2.70 g, 86% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.93 (br s, 1H), 9.99 (s, 1H), 9.04 (br s, 1H), 8.27(s, 1H), 7.43 (br d, J=6.0 Hz, 1H), 6.96 (d, J=8.0 Hz, 1H), 2.76 (s,3H), 1.55 (s, 9H).

Step 5—Tert-ButylN-[3-(hydroxyiminomethyl)-4-methyl-1H-indol-7-yl]carbamate

To a solution of tert-butyl N-(3-formyl-4-methyl-1H-indol-7-yl)carbamate(2.70 g, 9.84 mmol) in ethanol (80 mL) was added NH₂OH HCl (1.03 g, 14.7mmol) and anhydrous potassium acetate (2.90 g, 29.5 mmol). The mixturewas stirred at 80° C. for 30 minutes. On completion, the reactionmixture was concentrated in vacuo to get a residue. The residue wasdiluted with water (60 mL) and extracted with ethyl acetate (3×60 mL).The organic phase was collected, dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo to give the title compound (2.80 g,98% yield) as a white solid. LC-MS (ESI⁺) m/z 290.2 (M+H)⁺.

Step 6—Tert-Butyl N-(3-cyano-4-methyl-1H-indol-7-yl)carbamate

To a solution of tert-butylN-[3-(hydroxyiminomethyl)-4-methyl-1H-indol-7-yl]carbamate (2.60 g, 8.99mmol) in anhydrous tetrahydrofuran (70 mL) was addeddi(imidazol-1-yl)methanthione (3.20 g, 17.9 mmol) and the mixture wasstirred at rt for 2 h. The reaction mixture was then concentrated invacuo to get a residue. The residue was diluted with ice water (60 mL)and extracted with ethyl acetate (3×40 mL). The combined organic phasewas collected, dried over anhydrous magnesium sulfate, filtered andconcentrated in vacuo to get a residue. The residue was purified bycolumn chromatography (Petroleum ether:Ethyl acetate=5:1 to 2:1) to givethe title compound (2.40 g, 98% yield) as a gray solid. ¹H NMR (400 MHz,CDCl₃) δ 10.98 (br s, 1H), 7.74 (d, J=3.2 Hz, 1H), 6.89 (d, J=7.6 Hz,1H), 6.81 (br s, 1H), 6.66 (br d, J=6.8 Hz, 1H), 2.75 (s, 3H), 1.57 (s,9H).

Step 7—7-Amino-4-methyl-1H-indole-3-carbonitrile

To a solution of tert-butyl N-(3-cyano-4-methyl-1H-indol-7-yl)carbamate(2.30 g, 8.48 mmol) in anhydrous dichloromethane (23 mL) was addedtrifluoroacetic acid (17.7 g, 155 mmol, 11.50 mL). The mixture wasstirred at rt for 30 minutes. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. The residue was diluted withsaturated sodium bicarbonate solution (50 mL) and extracted with ethylacetate (3×30 mL). The combined organic phase was collected, dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thecrude product. The crude product was triturated with petroleumether:dichloromethane (30:1, 50 mL) to give the title compound (1.40 g,96% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (br s,1H), 8.12 (d, J=3.2 Hz, 1H), 6.67 (d, J=7.6 Hz, 1H), 6.37 (d, J=7.6 Hz,1H), 5.09 (br s, 2H), 2.50 (br s, 3H).

Step8—N-(3-cyano-4-methyl-1H-indol-7-yl)-4-[(1,3-dioxoisoindolin-2-yl)methyl]benzenesulfon-amide

To a solution of 4-[(1,3-dioxoisoindolin-2-yl)methyl]benzenesulfonylchloride (1.51 g, 4.50 mmol, Intermediate DG) in dichloromethane (30 mL)was added pyridine (646 mg, 8.18 mmol, 660 uL) and DMAP (49.9 mg, 408umol) and 7-amino-4-methyl-1H-indole-3-carbonitrile (700 mg, 4.09 mmol).The mixture was stirred at rt for 3 h. On completion, the reactionmixture was concentrated in vacuo to get a residue. The residue wastriturated with (dichloromethane:methanol=10:1, 50 mL) to give the titlecompound (1.00 g, 51% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.92 (d, J=2.4 Hz, 1H), 9.97 (s, 1H), 8.15 (d, J=3.2 Hz, 1H),7.93-7.84 (m, 4H), 7.67 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 6.76(d, J=8.4 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 4.83 (s, 2H), 2.55 (s, 3H).

Step9—4-(Aminomethyl)-N-(3-cyano-4-methyl-1H-indol-7-yl)benzenesulfonamide

To a solution ofN-(3-cyano-4-methyl-1H-indol-7-yl)-4-[(1,3-dioxoisoindolin-2-yl)methyl]-benzenesulfonamide (1.00 g, 2.13 mmol) in ethanol (30 mL) was added hydrazinehydrate (2.13 g, 2.07 mL). The mixture was stirred at 80° C. for 2 h. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (1.05 g, 92% yield) as a white solid. LC-MS (ESI⁺) m/z341.1 (M+H)⁺.

2-[2-[2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid (Intermediate DI)

Step 1—Ethyl2-[2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of tert-butylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(2.00 g, 5.93 mmol, synthesized via Step 1 of Intermediate AK) andRh₂(OAc)₄ (52.4 mg, 119 umol) in dichloromethane (10 mL) was added asolution of ethyl 2-diazoacetate (1.01 g, 8.89 mmol, 931 uL) dissolvedin dichloromethane (10 mL) dropwise at rt. Then the reaction mixture wasstirred at rt for 17 h. On completion, the reaction mixture was quenchedby adding water (15 mL) and was then extracted with dichloromethane(2×10 mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel column chromatography (Petroleumether:Ethyl acetate=5:1 to 1:1) to give the title compound (370 mg, 15%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 5.12 (s, 1H), 4.23(q, J=7.2 Hz, 2H), 4.16 (s, 2H), 3.76-3.64 (m, 16H), 3.56 (t, J=5.2 Hz,2H), 3.33 (d, J=4.8 Hz, 2H), 1.46 (s, 9H), 1.30 (t, J=7.2 Hz, 3H).

Step2—2-[2-[2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a mixed solution of ethyl2-[2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]-ethoxy]ethoxy]acetate(370 mg, 877 umol) in tetrahydrofuran (4 mL), methanol (1 mL) and H₂O (1mL) was added lithium hydroxide (41.8 mg, 1.75 mmol). The reactionmixture was stirred at rt for 0.5 hr. On completion, the reactionmixture was adjusted pH<7 with 1 N hydrochloride acid solution, and thenconcentrated in vacuo to give the title compound (520 mg, 70% purity,87% yield) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.33 (s,1H), 4.67 (s, 1H), 3.88 (s, 2H), 3.61-3.55 (m, 16H), 3.47 (t, J=5.2 Hz,2H), 3.23 (d, J=5.2 Hz, 2H), 1.37 (s, 9H).

4-(2-Aminoethylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate DJ)

Step 1—Tert-ButylN-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]carbamate

A mixture of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione(2.07 g, 7.49 mmol, Intermediate R), tert-butylN-(2-aminoethyl)carbamate (1.00 g, 6.24 mmol) and DIPEA (1.61 g, 12.5mmol, 2.17 mL) in dioxane (10 mL) was stirred at 115° C. for 12 hours.On completion, the mixture was concentrated in vacuo. The residue waspurified by column chromatography to give the title compound (0.90 g,28% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.58 (t, J=7.6 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.08-6.96 (m, 2H), 6.71(t, J=5.6 Hz, 1H), 5.05 (dd, J=5.6, 12.8 Hz, 1H), 3.41-3.35 (m, 2H),3.13 (m, 2H), 2.97-2.82 (m, 1H), 2.65-2.53 (m, 2H), 2.07-1.96 (m, 1H),1.37 (s, 9H).

Step2—4-(2-Aminoethylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]carbamate (0.30 g, 720 umol) in DCM (10 mL) was added HCl in dioxane (4N, 3 mL). The reaction mixture was stirred at rt for 0.5 hr. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (0.25 g, 98% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.12 (s, 1H), 7.63 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.4 Hz,1H), 7.10 (d, J=6.8 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 5.05 (dd, J=5.6,12.8 Hz, 1H), 3.62-3.57 (m, 2H), 3.01-2.89 (m, 2H), 2.90-2.89 (m, 1H),2.62-2.55 (m, 2H), 2.05-2.03 (m, 1H).

2-Chloro-N-cyclopropyl-5-ethynyl-pyridin-4-amine (Intermediate DL)

Step 1—5-Bromo-2-chloro-N-cyclopropyl-pyridin-4-amine

To a solution of 5-bromo-2,4-dichloro-pyridine (5 g, 22.0 mmol) andcyclopropanamine (1.32 g, 23.1 mmol) in DMF (50 mL) was added DIPEA(8.54 g, 66.1 mmol). The reaction mixture was stirred at 100° C. for 17h. On completion, the mixture was diluted with H₂O (40 mL) and extractedwith EA (2×40 mL). The organic layer was washed with brine (50 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the titlecompound (2.10 g, 39% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ8.14 (s, 1H), 6.90 (s, 1H), 5.22 (s, 1H), 2.56-2.49 (m, 1H), 0.96-0.90(m, 2H), 0.69-0.64 (m, 2H); LC-MS (ESI⁺) m/z 248.9 and 246.9 (M+H)⁺.

Step 2—2-Chloro-N-cyclopropyl-5-(2-trimethylsilylethynyl)pyridin-4-amine

5-Bromo-2-chloro-N-cyclopropyl-pyridin-4-amine (1.0 g, 4.0 mmol), CuI(46.2 mg, 242 umol) and Pd(PPh₃)₂Cl₂ (170 mg, 242 umol) was taken upinto a microwave tube. Then ethynyl(trimethyl)silane (794 mg, 8.08mmol), TEA (7.36 g, 72.7 mmol) and DMF (5 mL) were added into the abovetube. The mixture was degassed with nitrogen gas for 5 minutes. Thesealed tube was then heated to 120° C. for 1 h under microwave. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (900 mg, 45% yield) asa brown solid. LC-MS (ESI⁺) m/z 265.0 (M+H)⁺.

Step 3—2-Chloro-N-cyclopropyl-5-ethynyl-pyridin-4-amine

To a solution of2-chloro-N-cyclopropyl-5-(2-trimethylsilylethynyl)pyridin-4-amine (1.0g, 3.8 mmol) in a mixed solvent of MeOH (10 mL) and DCM (10 mL) wasadded K₂CO₃ (2.09 g, 15.1 mmol). The reaction mixture was stirred at rtfor 15 h. On completion, the mixture was filtered and concentrated invacuo. The residue was purified by silica gel chromatography to give thetitle compound (268 mg, 35% yield) as a yellow solid. ¹H NMR (300 MHz,CDCl₃) δ 8.13 (s, 1H), 6.88 (s, 1H), 5.42 (s, 1H), 3.50 (s, 1H),2.57-2.46 (m, 1H), 0.96-0.84 (m, 2H), 0.70-0.58 (m, 2H); LC-MS (ESI⁺)m/z 193.0 (M+H)⁺.

2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetic Acid(Intermediate DM)

Step 1—Ethyl 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]

To a mixture of tert-butylN-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (3.00 g, 12.0 mmol, CAS#139115-92-7) and Rh(OAc)₂ (106 mg, 481 umol) in DCM (70 mL) was added asolution of ethyl 2-diazoacetate (4.12 g, 36.1 mmol) in DCM (40 mL)dropwise. The reaction mixture was stirred at rt for 16 h. Oncompletion, the reaction mixture was diluted with water (100 mL) andextracted with DCM (3×100 mL). The combined organic layer was dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography to give the title compound(600 mg, 14% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ5.15-5.13 (m, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.16 (s, 2H), 3.77-3.69 (m,4H), 3.68-3.61 (m, 4H), 3.55 (t, J=5.2 Hz, 2H), 3.32 (d, J=4.8 Hz, 2H),1.45 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).

Step 2—2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]aceticAcid

To a solution of ethyl2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetate (300mg, 894 umol) in a mixed solvent of MeOH (5 mL) and H₂O (5 mL) was addedLiOH H₂O (75.0 mg, 1.79 mmol). The reaction mixture was stirred at rtfor 1 hour. On completion, the reaction mixture was concentrated invacuo. The residue was acidified with 1N HCl solution until the pH=7.The mixture was lyophilized to give the title compound (300 mg, 100%yield) as a white solid.

2-(2,6-Dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1,3-dione(Intermediate DN)

To a solution of prop-2-yn-1-amine (332 mg, 6.03 mmol, 386 uL) and DIPEA(3.90 g, 30.1 mmol, 5.25 mL) in dioxane (20.0 mL) was added2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (2.00 g, 7.24mmol, Intermediate R), and the mixture was stirred at 115° C. for 16 h.On completion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% FA) to give the titlecompound (550 mg, 29% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl3)δ 8.00 (s, 1H), 7.65-7.57 (m, 1H), 7.23 (d, J=7.2 Hz, 1H), 7.06 (d,J=8.4 Hz, 1H), 6.50-6.48 (m, 1H), 4.99-4.91 (m, 1H), 4.14-4.10 (m, 2H),2.91-2.77 (m, 2H), 2.31-2.28 (m, 1H), 2.20-2.11 (m, 1H), 2.07 (s, 1H).

4-(But-3-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate DO)

To a mixture of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione(2.04 g, 7.39 mmol, Intermediate R) and but-3-yn-1-amine (650 mg, 6.16mmol, hydrochloride) in dioxane (20 mL) was added DIPEA (7.96 g, 61.5mmol). The reaction mixture was stirred at 115° C. for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% FA) to give the title compound (800 mg,39% yield) as a green solid. LC-MS (ESI⁺) m/z 326.0 (M+H)⁺.

4-(3-Azidopropylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate DP)

To a solution of 3-azidopropan-1-amine (198 mg, 1.45 mmol, HCl, CAS#88192-19-2) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (0.40 g, 1.45mmol, Intermediate R) in DMF (10 mL) was added DIPEA (936 mg, 7.24 mmol,1.26 mL). The reaction mixture was stirred at 115° C. for 12 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by reverse phase chromatography(NH₃·H₂O) to give the title compound (200 mg, 38.4% yield) as a yellowsolid. LC-MS (ESI⁺) m/z 357.0 (M+H)⁺.

Tert-Butyl 4-(4-hydroxycyclohexyl)piperazine-1-carboxylate (IntermediateDO)

Step 1—Tert-butyl N,N-bis(2-chloroethyl)carbamate

To a mixture of 2-chloro-N-(2-chloroethyl)ethanamine (20.0 g, 112 mmol,HCl salt) in a mixed solution of DCM (150 mL) and NaOH (13.5 g, 3 M, 110mL) was added a solution of (Boc)₂O (24.5 g, 112 mmol) in DCM (80 mL)dropwise. The reaction mixture was stirred at rt for 18 h. Oncompletion, the mixture was separated and the organic layer was washedwith brine (300 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (24.5 g, 90% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.71-3.58 (m, 8H), 1.49 (s,9H).

Step 2—Tert-Butyl 4-(4-hydroxycyclohexyl)piperazine-1-carboxylate

To a solution of tert-butyl N,N-bis(2-chloroethyl)carbamate (10.0 g,41.3 mmol) and 4-aminocyclohexanol (5.04 g, 43.8 mmol) in dioxane (200mL) was added K₂CO₃ (17.1 g, 124 mmol) and KI (20.6 g, 124 mmol). Thereaction mixture was stirred at 115° C. for 17 h. On completion, thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatography to give thetitle compound (3.50 g, 30% yield) as a red solid. ¹H NMR (400 MHz,MeOH-d₄) δ 3.54-3.47 (m, 1H), 3.47-3.39 (m, 4H), 2.60-2.51 (m, 4H),2.37-2.27 (m, 1H), 2.03-1.97 (m, 2H), 1.96-1.90 (m, 2H), 1.47 (s, 9H),1.38-1.27 (m, 4H).

(2S)-2-Hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propenamide(Intermediate DR)

Step 1—Ethyl2-amino-4-(2-ethoxy-2-oxo-ethyl)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate

To a solution of ethyl 2-(2-oxocyclopentyl)acetate (30.0 g, 169 mmol) inEtOH (300 mL) was added ethyl 2-cyanoacetate (17.2 g, 152 mmol), Et₂NH(15.2 g, 208 mmol,) and sulphur (6.62 g, 206 mmol) at rt and the mixturewas stirred for 90 h. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. The residue was diluted with EA(300 mL) and washed with brine (3×40 mL). The organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (SiO₂, PE:EA=10:1) to givethe title compound (25.0 g, 47% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 5.95 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H),3.64-3.55 (m, 1H), 2.87-2.11 (m, 6H), 1.35 (t, J=7.2 Hz, 3H), 1.25 (t,J=7.2 Hz, 3H); LC-MS (ESI⁺) m/z 298.0 (M+H)⁺.

Step 2—Ethyl2-(1-hydroxy-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-c]pyrimidin-8-yl)acetate

A mixture of ethyl2-amino-4-(2-ethoxy-2-oxo-ethyl)-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate(28.0 g, 94.1 mmol) and formamide (158 g, 3.51 mol) was stirred at 180°C. for 8 h. On completion, the reaction mixture was cooled to roomtemperature and then quenched with water/ice (200 mL). The mixture wasextracted with ethyl acetate (3×100 mL) and the combined organic layerwas dried over anhydrous Na₂SO4, filtered and concentrated in vacuo togive the title compound (15.0 g, 57% yield) as a yellow brown solid. ¹HNMR (400 MHz, DMSO-d₆) δ 12.49 (s, 1H), 8.03 (s, 1H), 4.05 (q, J=7.2 Hz,2H), 3.66-3.52 (m, 1H), 3.28 (dd, J=3.6, 16 Hz, 1H), 3.08-2.81 (m, 2H),2.74-2.59 (m, 1H), 2.40-2.30 (m, 1H), 2.18-1.99 (m, 1H), 1.15 (t, J=7.2Hz, 3H); LC-MS (ESI⁺) m/z 279.0 (M+H)⁺.

Step 3—Ethyl2-(1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl)acetate

A mixture of ethyl2-(1-hydroxy-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-c]pyrimidin-8-yl)acetate(14.0 g, 50.3 mmol) in POCl₃ (165 g, 1.08 mol) was stirred at 85° C. for16 h. On completion, the reaction mixture was concentrated in vacuo togive a residue. The residue was purified by column chromatography (SiO₂,PE:EA=5:1) to give the title compound (12.0 g, 80% yield) as a lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.71-8.63 (m, 1H), 4.07 (q, J=7.2Hz, 2H), 3.93-3.83 (m, 1H), 3.16-3.04 (m, 1H), 3.00-2.90 (m, 1H), 2.85(dd, J=2.8, 12.8 Hz, 1H), 2.73-2.67 (m, 1H), 2.42 (dd, J=10.4, 15.2 Hz,1H), 2.34-2.28 (m, 1H), 1.15 (t, J=7.2 Hz, 3H); LC-MS (ESI⁺) m/z 297.0(M+H)⁺.

Step4—2-(1-Chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl)ethanol

To a solution of ethyl2-(1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl)acetate(18.0 g, 60.6 mmol) in THF (200 mL) was added DIBAL-H (1 M, 196 mL) at−50° C. dropwise. Then the mixture was stirred at −30° C. for 1 hour. Oncompletion, the mixture was added to water (10 mL) and NaOH solution(15%, 20 mL) at 0° C. The mixture was then filtered and dried overNa₂SO₄, then filtered again and concentrated in vacuo to give a residue.The residue was purified by column chromatography (SiO₂, PE:EA=5:1) togive the title compound (12.0 g, 68% yield) as a light yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.76 (s, 1H), 3.85-3.71 (m, 2H), 3.62 (t, J=8.8Hz, 1H), 3.21-3.07 (m, 1H), 3.06-2.93 (m, 1H), 2.70-2.60 (m, 1H),2.44-2.33 (m, 1H), 2.20-2.08 (m, 1H), 1.78-1.68 (m, 1H); LC-MS (ESI⁺)m/z 254.9 (M+H)⁺.

Step5—2-[(8R)-1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl]ethanol

The racemic2-(1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl)ethanol(23.0 g, 90.2 mmol) was separated by SFC (column: AD (250 mm*30 mm, 10um); mobile phase: [0.1% NH₃H₂O MEOH]) to give to give two isomers. Thefirst fraction was the desired product:2-[(8R)-1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl]ethanol(10.9 g, 47% yield, tR=2.562) which was isolated as a yellow solid. Thesecond fraction is2-[(8S)-1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl]ethanol (11.5 g, 49% yield, tR=3.522) was also isolated as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.72 (s, 1H), 3.87-3.72 (m, 2H),3.70-3.59 (m, 1H), 3.21-3.09 (m, 11H), 3.06-2.95 (m, 1H), 2.71-2.61 (m,1H), 2.41-2.35 (m, 1H), 2.19-2.09 (m, 1H), 1.78-1.69 (m, 1H); LC-MS(ESI⁺) m/z 255.0 (M+H)⁺.

Step6—Tert-butyl-[2-[(8R)-1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl]ethoxy]-dimethyl-silane

To a solution of2-[(8R)-1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl]ethanol (5.9 g, 23.1 mmol) in DMF (60 mL) was added imidazole (2.21 g,32.4 mmol) and TBSCl (4.19 g, 27.7 mmol). The reaction mixture wasstirred at rt for 13 h under nitrogen atmosphere. On completion, thereaction mixture was diluted with water (30 mL) and extracted with EA(3×30 mL). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (PE:EA=5:1) to give the title compound (7.80g, 87% yield) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.74 (s,1H), 3.82-3.70 (m, 2H), 3.68-3.58 (m, 1H), 3.20-3.09 (m, 1H), 3.05-2.95(m, 1H), 2.68-2.58 (m, 1H), 2.48-2.37 (m, 1H), 2.17-2.05 (m, 1H),1.70-1.63 (m, 1H), 0.89 (s, 9H), 0.06 (d, J=0.8 Hz, 6H); LC-MS (ESI⁺)m/z 369.0 (M+H)⁺.

Step 7—Tert-butyl4-[4-[[(8R)-8-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate

To a solution of tert-butyl4-(4-hydroxycyclohexyl)piperazine-1-carboxylate (4.32 g, 15.1 mmol,Intermediate DQ) in THF (80 mL) was added NaH (1.73 g, 43.3 mmol, 60%dispersion in mineral oil) at 0° C. The reaction mixture was stirred at0° C. for 1 hour, then a solution oftert-butyl-[2-[(8R)-1-chloro-7,8-dihydro-6H-cyclopenta[3,4]thieno[1,3-d]pyrimidin-8-yl]ethoxy]-dimethyl-silane (4.00 g, 10.8mmol) in THF (40 mL) was added at 0° C. dropwise. The reaction mixturewas then heated to 60° C. and stirred for 14 h. On completion, thereaction mixture was quenched with water (50 mL) and the mixture wasextracted with EA (3×80 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (PE:EA=3:1) to givethe title compound (4.00 g, 42% yield) as a light yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 8.49 (s, 1H), 5.27-5.14 (m, 1H), 3.77-3.63 (m, 2H),3.50-3.40 (m, 5H), 3.14-3.01 (m, 1H), 2.99-2.87 (m, 1H), 2.68-2.57 (m,1H), 2.56-2.47 (m, 4H), 2.43-2.37 (m, 1H), 2.36-2.19 (m, 4H), 1.97 (d,J=10.4 Hz, 2H), 1.64-1.51 (m, 5H), 1.47 (s, 9H), 0.90 (s, 9H), 0.05 (s,6H); LC-MS (ESI⁺) m/z 617.2 (M+H)⁺.

Step 8—Tert-Butyl4-[4-[[(8R)-8-(2-hydroxyethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[4-[[(8R)-8-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(12.0 g, 19.4 mmol) in THF (120 mL) was added TBAF (1 M, 29.1 mL), andthe mixture was stirred at rt for 14 h. On completion, the reactionmixture was quenched by addition of water (100 mL), and then extractedwith EA (3×200 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (PE:EA=1:1) to give the titlecompound (9.7 g, 93% yield) as a light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 8.50 (s, 1H), 5.29-5.16 (m, 1H), 3.79-3.67 (m, 2H), 3.52-3.40(m, 5H), 3.14-3.02 (m, 1H), 2.96-2.90 (m, 1H), 2.71-2.62 (m, 1H),2.58-2.48 (m, 4H), 2.47-2.39 (m, 1H), 2.38-2.25 (m, 3H), 2.21-2.12 (m,1H), 2.03-1.92 (m, 2H), 1.81-1.70 (m, 2H), 1.65-1.49 (m, 4H), 1.47 (s,9H). LC-MS (ESI⁺) m/z 503.2 (M+H)⁺.

Step 9—Tert-Butyl4-[4-[[(8R)-8-(2-oxoethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[4-[[(8R)-8-(2-hydroxyethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate (9.70 g,19.3 mmol) in DCM (160 mL) was added DMP (16.3 g, 38.5 mmol) at 0° C.Then the mixture was allowed to warm to rt and stirred for 16 h. Oncompletion, the reaction mixture was quenched by saturated NaHCO₃ (200mL) and then extracted with DCM (3×200 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatography(PE:EA=1:1) to give the title compound (9.00 g, 72% yield) as a yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 9.84 (s, 1H), 8.52 (s, 1H), 5.28-5.17 (m,1H), 3.48 (t, J=5.2 Hz, 1H), 3.58-3.48 (m, 4H), 3.16-2.98 (m, 3H),2.88-2.76 (m, 1H), 2.74-2.52 (m, 6H), 2.38-2.27 (m, 2H), 2.18-2.11 (m,1H), 2.05-1.98 (m, 2H), 1.60-1.50 (m, 4H), 1.47 (s, 9H); LC-MS (ESI⁺)m/z 501.2 (M+H)⁺.

Step 10—Tert-Butyl4-[4-[[(8R)-8-(2-cyano-2-trimethylsilyloxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate andtert-butyl4-[4-[[(8R)-8-(2-cyano-2-hydroxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[4-[[(8R)-8-(2-oxoethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate (6.00 g, 11.98mmol) and TEA (1.21 g, 11.9 mmol) in DCM (80 mL) was added TMSCN (3.57g, 35.9 mmol), and the mixture was stirred at rt for 4 h. On completion,the reaction mixture was diluted with water (60 mL) and extracted withDCM (3×80 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give tert-butyl4-[4-[[(8R)-8-(2-cyano-2-trimethylsilyloxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate (5.5g) and tert-butyl4-[4-[[(8R)-8-(2-cyano-2-hydroxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(0.5 g) as a yellow oil, which were brought on to the next step as amixture. LC-MS (ESI⁺) m/z 600.3 (M+H)⁺.

Step 11—Tert-Butyl4-[4-[[(8R)-8-(2-cyano-2-hydroxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[4-[[(8R)-8-(2-cyano-2-trimethylsilyloxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(5.50 g, 9.17 mmol) and tert-butyl4-[4-[[(8R)-8-(2-cyano-2-hydroxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate (500 mg,947 umol) in THF (80 mL) was added TBAF (1 M, 13.75 mL), and the mixturewas stirred at rt for 3 h. On completion, the reaction mixture wasquenched with water (80 mL), and then extracted with EA (3×100 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (PE:EA=1:1) to give the title compound (4.20g, 69% yield) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (d,J=1.6 Hz, 1H), 5.32-5.18 (m, 1H), 4.58-4.50 (m, 1H), 3.69-3.37 (m, 5H),3.17-2.92 (m, 2H), 2.80-2.66 (m, 1H), 2.65-2.46 (m, 6H), 2.43-2.23 (m,3H), 2.04-1.85 (m, 3H), 1.76-1.49 (m, 4H), 1.46 (s, 9H). LC-MS (ESI⁺)m/z 528.1 (M+H)⁺.

Step12—2-Hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide

To a solution of tert-butyl4-[4-[[(8R)-8-(2-cyano-2-hydroxy-ethyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(4.20 g, 7.96 mmol) in DCM (80 mL) was added HCl in dioxane (4 M, 33.6mL), and the mixture was stirred at rt for 3 h. On completion, thereaction mixture was quenched with saturated sodium bicarbonate (30 mL).The mixture was concentrated in vacuo to give the title compound (4.00g, 100% yield) as a light yellow solid. LC-MS (ESI⁺) m/z 446.2 (M+H)⁺.

Step 13—Tert-butyl4-[4-[[(8R)-8-(3-amino-2-hydroxy-3-oxo-propyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate

To a solution of2-hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide (2.50 g, 5.61 mmol) in a mixedsolvent of DCM (25 mL) and MeOH (25 mL) was added TEA (1.70 g, 16.8mmol) and Boc₂0 (2.45 g, 11.2 mmol), and the mixture was stirred at rtfor 16 h. On completion, the reaction mixture was concentrated in vacuoto give a residue. The residue was purified by reverse phasechromatography (0.1% NH₃ H2O) to give the title compound (1.50 g, 47%yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=5.2 Hz,1H), 6.70-6.50 (m, 1H), 6.01-5.87 (m, 1H), 5.29-5.13 (m, 1H), 4.20-4.13(m, 1H), 3.72-3.53 (m, 1H), 3.42 (t, J=4.4 Hz, 4H), 3.15-3.04 (m, 1H),3.01-2.88 (m, 1H), 2.78-2.60 (m, 1H), 2.58-2.49 (m, 4H), 2.49-2.12 (m,6H), 1.99-1.83 (m, 3H), 1.63-1.43 (m, 13H). LC-MS (ESI⁺) m/z 546.2(M+H)⁺.

Step 14—Tert-Butyl4-[4-[[(8R)-8-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate

The racemic tert-butyl4-[4-[[(8R)-8-(3-amino-2-hydroxy-3-oxo-propyl)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(1.50 g, 2.66 mmol) was separated by SFC (column: AD (250 mm*30 mm, 10um); mobile phase: [0.1% NH₃H₂O ETOH]) to give the two isomers. Thefirst fraction is tert-butyl4-[4-[[(8R)-8-[(2R)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(700 mg, 46% yield, tR=1.034) which was isolated as a light yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 6.66 (d, J=2.8 Hz, 1H),5.99 (d, J=2.8 Hz, 1H), 5.25-5.11 (m, 1H), 4.21-4.10 (m, 1H), 3.67-3.56(m, 1H), 3.47-3.29 (m, 4H), 3.13-3.01 (m, 1H), 2.98-2.86 (m, 1H),2.70-2.57 (m, 1H), 2.54-2.43 (m, 4H), 2.40-2.04 (m, 6H), 1.97-1.79 (m,3H), 1.75-1.26 (m, 13H); LC-MS (ESI⁺) m/z 546.2 (M+H)⁺.

The second fraction was the desired4-[4-[[(8R)-8-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(560 mg, 37% yield, tR=1.238) was also isolated as a light yellow solid.¹H NMR (400 MHz, CDCl₃) δ 8.50 (s, 1H), 6.60 (d, J=2.8 Hz, 1H), 5.72 (d,J=2.8 Hz, 1H), 5.30-5.23 (m, 1H), 4.18-4.10 (m, 1H), 3.63-3.51 (m, 1H),3.48-3.36 (m, 4H), 3.18-3.05 (m, 1H), 3.00-2.88 (m, 1H), 2.81-2.66 (m,1H), 2.55-2.59 (m, 4H), 2.45-2.23 (m, 6H), 2.05-1.81 (m, 3H), 1.66-1.44(m, 13H); LC-MS (ESI⁺) m/z 546.3 (M+H)⁺.

Step 15—(2S)-2-Hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide

To a solution of tert-butyl4-[4-[[(8R)-8-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(80.0 mg, 143 umol) in DCM (2 mL) was added HCl in dioxane (4 M, 1.37mL), and the mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(80 mg, 100% yield, HCl salt) as a white solid; LC-MS (ESI⁺) m/z 446.1(M+H)⁺.

Tert-Butyl 2-(2-aminoethoxy)acetate (Intermediate DS)

Step 1—Tert-Butyl 2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]acetate

To a solution of 2-(2-hydroxyethyl)isoindoline-1,3-dione (1.00 g, 5.23mmol, CAS #3891-07-4) and Rh(OAc)₂ (46.2 mg, 209 umol) in DCM (20 mL)was added tert-butyl 2-diazoacetate (1.64 g, 11.5 mmol) in DCM (20 mL)dropwise at rt over 1 hour. The reaction mixture was then stirred at rtfor 20 hours. On completion, the mixture was concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the titlecompound (0.76 g, 48% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.90-7.84 (m, 2H), 7.77-7.70 (m, 2H), 3.99 (s, 2H), 3.97-3.93 (m, 2H),3.85-3.80 (m, 2H), 1.45 (s, 9H); LC-MS (ESI⁺) m/z 328.0 (M+Na)⁺.

Step 2—Tert-Butyl 2-(2-aminoethoxy)acetate

To a solution of tert-butyl2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]acetate (0.76 g, 2.49 mmol) inEtOH (20 mL) was added NH₂NH₂ H2O (623 mg, 12.5 mmol). The reactionmixture was stirred at 80° C. for 2 hours. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo. The residue wasdiluted with DCM (20 mL), filtered and the filtrate was concentrated invacuo to give the title compound (340 mg, 78% yield) as a yellow oil.LC-MS (ESI⁺) m/z 176.0 (M+H)⁺.

2-[2-[2-[2-[2-(2-ethoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid (Intermediate DT)

Step 1—Ethyl2-[2-[2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]acetate (1.00 g, 3.57mmol, synthesized via Step 1 of Intermediate BK) and Rh(OAc)₂ (39.5 mg,178 umol) in DCM (20 mL) was added a solution of tert-butyl2-diazoacetate (1.01 g, 7.14 mmol) in DCM (30 mL) dropwise at rt over 30minutes. The reaction mixture was then stirred at rt for an additional17 hours. On completion, the mixture was washed with water (3×30 mL).The organic phase was separated and was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (0.64 g, 45% yield) as ayellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.23 (q, J=7.2 Hz, 2H), 4.17 (s,2H), 4.04 (s, 2H), 3.78-3.66 (m, 16H), 1.49 (s, 9H), 1.30 (t, J=7.2 Hz,3H).

Step2—2-[2-[2-[2-[2-(2-ethoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a solution of ethyl2-[2-[2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate(200 mg, 507 umol) in DCM (1.5 mL) was added TFA (1.5 mL). The reactionmixture was stirred at rt for 30 minutes. On completion, the mixture wasconcentrated in vacuo to give the title compound (170 mg, 99% yield) asa yellow oil.

(4-Hydroxycyclohexyl) 4-methylbenzenesulfonate (Intermediate DU)

To a solution of pyridine (12.3 g, 155 mmol) in CHCl₃ (150 mL) was addedcyclohexane-1,4-diol (15.0 g, 129 mmol) at rt. Then the mixture was thencooled to 0° C. and 4-methylbenzenesulfonyl chloride (24.6 g, 129 mmol)was added into the mixture. The reaction mixture was then allowed towarm to rt and stirred for 18 hrs. On completion, the reaction mixturewas acidified with 1N HCl solution until the pH=5-6, and extracted withEA (3×30 mL). The organic layer was washed with brine (50 mL), driedover Na₂SO₄, and concentrated in vacuo. The residue was purified bysilica gel chromatography to give the title compound (16.0 g, 46% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.85-7.76 (m, 2H), 7.36 (d,J=8.0 Hz, 2H), 4.66-4.49 (m, 1H), 3.80-3.70 (m, 1H), 2.47 (s, 3H),1.97-1.91 (m, 2H), 1.72-1.65 (m, 2H), 1.64-1.50 (m, 4H).

Tert-Butyl4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine-1-carboxylate

Step 1—Tert-Butyl 4-((4-bromophenyl)sulfonyl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (20.1 g, 108 mmol)in THF (250 mL) was added TEA (19.8 g, 196 mmol) at 0° C. The mixturewas stirred at 0° C. for 10 minutes, then 4-bromobenzenesulfonylchloride (25.0 g, 97.8 mmol) was added to the reaction mixture.The reaction mixture was then allowed to warm to rt and stirred for 50minutes. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was washed with water (100 mL) and10% HCl (50 mL), and then extracted with DCM (2×50 mL). The organiclayer was washed with NaHCO₃ (50 mL) until the pH=8. The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was purified by columnchromatography (petroleum ether/ethyl acetate=0:1) to give the titlecompound (33 g, 83% yield)) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.72-7.70 (m, 2H), 7.64-7.62 (m, 2H), 3.54 (t, J=4.8 Hz, 4H), 3.00 (t,J=4.8 Hz, 4H), 1.43 (s, 9H).

Step 2—Tert-Butyl4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)piperazine-1-carboxylate

To a solution of tert-butyl4-(4-bromophenyl)sulfonylpiperazine-1-carboxylate (10.0 g, 24.7 mmol)and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(18.8 g, 74.0 mmol) in dioxane (100 mL) was added Pd(dppf)Cl₂ (1.81 g,2.47 mmol) and KOAc (4.84 g, 49.4 mmol). The reaction mixture wasstirred at 80° C. for 3 hours. On completion, the mixture was filtered,and the filter was concentrated in vacuo to give a residue. The residuewas purified by flash silica gel chromatography (Ethyl acetate:Petroleumether=1/1) to give the title compound (8.00 g, 63% yield) as a graysolid. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (d, J=8.0 Hz, 2H), 7.74 (d, J=8.0Hz, 2H), 3.52 (t, J=4.8 Hz, 4H), 2.98 (t, J=4.8 Hz, 4H), 1.42 (s, 9H),1.37 (s, 12H), LC-MS (ESI⁺) m/z 397.0 (M+H−56)⁺.

Ethyl 2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetate(Intermediate DW)

To a solution of ethyl2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetate(0.80 g, 2.11 mmol, synthesized via Steps 1-4 of Intermediate CH) in DCM(10 mL) was added HCl in dioxane (4 M, 2.67 mL). The reaction mixturewas stirred at rt for 15 minutes. On completion, the reaction mixturewas concentrated in vacuo to give the title compound (0.55 g, 83% yield,HCl) as a yellow oil.

Tert-Butyl 2-(8-aminooctoxy)acetate (Intermediate DX)

Step 1—8-Hydroxyoctyl 4-methylbenzenesulfonate

To a mixture of octane-1,8-diol (23.5 g, 160 mmol, CAS #629-41-4) andpyridine (10.1 g, 128 mmol) in DCM (360 mL) was added a solution of TsCl(24.5 g, 128 mmol) in DCM (240 mL) dropwise. The mixture was thenstirred at rt for 16 hours. On completion, the mixture was washed with1N HCl (2×50 mL). The organic layer was dried with Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=3: 1) to givethe title compound (10.0 g, 20% yield) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 7.80 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 4.02 (t,J=6.4 Hz, 2H), 3.63 (t, J=6.4 Hz, 2H), 2.45 (s, 3H), 1.69-1.60 (m, 2H),1.56-1.53 (m, 2H), 1.36-1.23 (m, 8H); LC-MS (ESI⁺) m/z 323.0 (M+Na)⁺.

Step 2—2-(8-Hydroxyoctyl)isoindoline-1,3-dione

To a solution of 8-hydroxyoctyl 4-methylbenzenesulfonate (5.00 g, 16.6mmol) in DMF (80 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (4.01g, 21.6 mmol). The mixture was stirred at 100° C. for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was diluted with DCM (50 mL), filtered and thefiltrate was concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (PE/EA=3/1) to give the titlecompound (4.50 g, 98% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.86-7.79 (m, 2H), 7.74-7.66 (m, 2H), 3.69-3.59 (m, 4H), 1.76-1.46 (m,6H), 1.32-1.29 (m, 6H).

Step 3—Tert-Butyl 2-[8-(1,3-dioxoisoindolin-2-yl)octoxy]acetate

To a solution of 2-(8-hydroxyoctyl)isoindoline-1,3-dione (3.00 g, 10.9mmol) and Rh(OAc)₂ (120 mg, 544 umol) in DCM (20 mL) was added asolution of tert-butyl 2-diazoacetate (2.32 g, 16.3 mmol) in DCM (80 mL)dropwise. The reaction mixture was stirred at rt for 48 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatography(PE/EA=2/1) to give the title compound (1.40 g, 26% yield) as a lightyellow oil. LC-MS (ESI⁺) m/z 412.2 (M+Na)⁺.

Step 4—Tert-Butyl 2-(8-aminooctoxy)acetate

To a solution of tert-butyl2-[8-(1,3-dioxoisoindolin-2-yl)octoxy]acetate (1.4 g, 2.91 mmol) in EtOH(25 mL) was added N₂H₄ H2O (1.49 g, 29.1 mmol). Then the reactionmixture was stirred at 80° C. for 16 hours. On completion, the reactionmixture was filtered. The filtrate was concentrated in vacuo to give thetitle compound (750 mg, 99% yield) as a light yellow oil. LC-MS (ESI⁺)m/z 260.2 (M+H)⁺.

Methyl 5-(4-amino-3-carbamoyl-pyrazol-1-yl)pyridine-2-carboxylateIntermediate DY)

Step 1—Ethyl 1-(6-bromo-3-pyridyl)-4-nitro-pyrazole-3-carboxylate

To a solution of ethyl 4-nitro-1H-pyrazole-3-carboxylate (5.8 g, 31.3mmol, CAS #55864-87-4), pyridine (9.91 g, 125 mmol) and Cu(OAc)₂ (8.54g, 46.9 mmol) in DCM (120 mL) was added (6-bromo-3-pyridyl)boronic acid(7.59 g, 37.5 mmol, CAS #223463-14-7). The mixture was stirred at rt for16 hours under an oxygen atmosphere (15 psi pressure). On completion,the reaction mixture was quenched by adding saturated NH₃ H₂O solution(40 mL). The organic layer was separated and dried over Na₂SO₄, filteredand concentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (PE/EA=3/1) to give the title compound (2.30g, 21% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s,1H), 9.00 (d, J=2.8 Hz, 1H), 8.31 (dd, J=3.2, 8.8 Hz, 1H), 7.91 (d,J=8.8 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).

Step 2—1-(6-Bromo-3-pyridyl)-4-nitro-pyrazole-3-carboxamide

To a solution of ethyl1-(6-bromo-3-pyridyl)-4-nitro-pyrazole-3-carboxylate (2.30 g, 6.74 mmol)in THF (15 mL) was added NH₃—H₂O (1.03 mmol, 25 mL, 30% solution) in asealed tube, and the mixture was stirred at 80° C. for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (1.80 g, 72% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.74 (s, 1H), 9.03 (d, J=3.2 Hz, 1H), 8.32 (dd, J=2.8, 8.8Hz, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=8.8 Hz, 1H); LC-MS(ESI⁺) m/z 311.9 (M+H)⁺.

Step 3—4-Amino-1-(6-bromo-3-pyridyl)pyrazole-3-carboxamide

To a solution of 1-(6-bromo-3-pyridyl)-4-nitro-pyrazole-3-carboxamide(1.80 g, 4.90 mmol) in a mixed solvent of MeOH (45 mL) and H₂O (10 mL)was added Fe (2.74 g, 49.0 mmol) and NH₄Cl (2.62 g, 49.0 mmol). Themixture was stirred at 70° C. for 36 hours. On completion, the reactionmixture was filtered and the filtrate was concentrated in vacuo to givea residue. The residue was triturated with water (20 mL), filtered andthe filter cake was dried in vacuo to give the title compound (0.90 g,65% yield) as a brown solid. LC-MS (ESI⁺) m/z 282.0 (M+H)⁺.

Step 4—Methyl 5-(4-amino-3-carbamoyl-pyrazol-1-yl)pyridine-2-carboxylate

To a solution of 4-amino-1-(6-bromo-3-pyridyl)pyrazole-3-carboxamide(450 mg, 1.60 mmol) in a mixed solvent of DMF (15 mL) and MeOH (15 mL)was added Pd(dppf)Cl₂ (46.6 mg, 63.8 umol) and TEA (161 mg, 1.60 mmol).The suspension was degassed under vacuum and purged with CO three times.The mixture was stirred at 80° C. for 16 hours under CO (50 psipressure). On completion, the reaction mixture was concentrated in vacuoto give a residue. The residue was purified by silica gel columnchromatography (Petroleum ether/Ethyl acetate=1/1) to give the titlecompound (400 mg, 94% yield) as a brown solid. LC-MS (ESI⁺) m/z 262.0(M+H)⁺.

5-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoylpyrazol-1-yl]pyridine-2-carboxylicAcid (Intermediate DZ)

Step 1—Methyl5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]pyridine-2-carboxylate

To a solution of2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (494 mg, 1.28 mmol, Intermediate CM) in DMF (6 mL) was added HATU(630 mg, 1.66 mmol) and DIPEA (494.54 mg, 3.83 mmol). The mixture wasstirred at rt for 12 minutes, then methyl5-(4-amino-3-carbamoyl-pyrazol-1-yl)pyridine-2-carboxylate (340 mg, 1.28mmol, Intermediate DY) was added, and the mixture was stirred at rt for2 hours. On completion, the reaction mixture was concentrated in vacuoto give a residue. The residue was purified by silica gel chromatographyto give the title compound (500 mg, 49% yield) as a yellow solid. LC-MS(ESI⁺) m/z 631.2 (M+H)⁺.

Step2—5-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoylpyrazol-1-ylpyridine-2-carboxylicAcid

To a mixture of methyl5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]pyridine-2-carboxylate(500 mg, 792 umol) in a mixed solvent of THF (5 mL), MeOH (1 mL) and H₂O(1 mL) was added LiOH (94.9 mg, 3.96 mmol). The reaction mixture wasstirred at rt for 2 hours. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (500 mg, 90% yield) asa brown solid. LC-MS (ESI⁺) m/z 617.2 (M+H)⁺.

Tert-ButylN-[(1S,2R)-2-[(2-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino]cyclohexyl]Carbamate(Intermediate EA)

Step 1 —(2-Bromopyrazolo[1,5-a]pyrimidin-5-yl)oxysodium

To a solution of Na (7.10 g, 309 mmol) in EtOH (125 mL) was added3-bromo-1H-pyrazol-5-amine (5.00 g, 30.9 mmol, CAS #1203705-55-8) and1,3-dimethylpyrimidine-2,4-dione (4.33 g, 30.9 mmol, CAS #874-14-6). Thereaction mixture was stirred at 80° C. for 3 hours. On completion, themixture was cooled to 0-5° C., then filtered. The filter cake was washedwith cold EtOH, and dried in vacuo to give the title compound (2.80 g,38% yield) as a yellow solid. ¹H NMR (400 MHz, D₂O) 6 8.02 (d, J=7.6 Hz,1H), 5.98 (d, J=7.6 Hz, 1H), 5.85 (s, 1H).

Step 2—2-Bromo-5-chloro-pyrazolo[1,5-a]pyrimidine

A mixture of (2-bromopyrazolo[1,5-a]pyrimidin-5-yl)oxysodium (1.00 g,4.24 mmol) in POCl₃ (10 mL) was stirred at 110° C. for 3 hours. Oncompletion, the mixture was concentrated in vacuo. The residue wasdiluted with EA (20 mL), washed with NaHCO₃ (10 ml), and concentrated invacuo. The residue was purified by silica gel chromatography to give thetitle compound (0.67 g, 68% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.51 (d, J=7.2 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.69 (s, 1H).

Step 3—Tert-ButylN-[(1S,2R)-2-[(2-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino]cyclohexyl]carbamate

2-bromo-5-chloro-pyrazolo[1,5-a]pyrimidine (620 mg, 2.67 mmol),tert-butyl N-[(1S,2R)-2-amino cyclohexyl]carbamate (686 mg, 3.20 mmol,CAS #184954-75-4) and DIPEA (379 mg, 2.93 mmol) were taken up into amicrowave tube in NMP (6 mL). The sealed tube was heated at 130° C. for3 hours under microwave. On completion, the mixture was concentrated invacuo to remove the solvent. Then the residue was purified by silica gelchromatography to give the title compound (1.00 g, 91% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.08 (d, J=7.6 Hz, 1H), 6.10 (s, 1H),5.98 (d, J=7.6 Hz, 1H), 5.76 (s, 1H), 4.94 (br s, 1H), 4.20-4.11 (m,1H), 4.01-3.92 (m, 1H), 2.00-1.83 (m, 1H), 1.75-1.49 (m, 6H), 1.45 (s,9H), 1.39-1.22 (m, 1H).

Methyl4-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]benzoate(Intermediate EB)

Step 1—Methyl 4-(3-formyl-1H-pyrazol-1-yl)benzoate

To a solution of 1H-pyrazole-3-carbaldehyde (10.0 g, 104 mmol, CAS#3920-20-1) and (4-methoxy carbonyl-phenyl) boronic acid (22.5 g, 125mmol, CAS #99768-12-4) in DCM (50 mL) was added Cu(OAc)₂ (22.7 g, 125mmol) and pyridine (32.9 g, 416 mmol). The reaction mixture was stirredat rt for 18 hours under oxygen gas (balloon). On completion, themixture was concentrated in vacuo. The residue was purified by silicagel chromatography to give the title compound (12.0 g, 50% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.24-8.14 (m, 2H),8.06 (d, J=2.4 Hz, 1H), 7.90-7.82 (m, 2H), 7.02 (d, J=2.4 Hz, 1H), 3.95(s, 3H).

Step 2—Methyl 4-(4-bromo-3-formyl-1H-pyrazol-1-yl)benzoate

To a solution of methyl 4-(3-formylpyrazol-1-yl)benzoate (4.00 g, 17.4mmol) in DMF (40 mL) was added NBS (6.18 g, 34.8 mmol). The reactionmixture was stirred at rt for 1 hour. Then, the reaction mixture washeated to 50° C. and stirred for 12 hours. On completion, the mixturewas concentrated in vacuo. The residue was purified by prep-HPLC (0.1%FA) to give the title compound (4.50 g, 82% yield) as a white solid. ¹HNMR (400 MHz, CDCl₃) δ 10.02 (s, 1H), 8.12 (d, J=8.4 Hz, 2H) 8.04 (s,1H), 7.75 (d, J=8.4 Hz, 2H), 3.89 (s, 3H); LC-MS (ESI⁺) m/z 308.9, 310.9(M+1)⁺.

Step 3—Methyl 4-(4-bromo-3-(difluoromethyl)-1H-pyrazol-1-yl)benzoate

To a solution of methyl 4-(4-bromo-3-formyl-pyrazol-1-yl)benzoate (1.70g, 5.50 mmol) in DCM (100 mL) was added DAST (7.98 g, 49.5 mmol) at 0°C. The reaction mixture was then allowed to warm to rt and stirred for 5hours. On completion, the mixture was quenched with methanol (30 mL) at0° C. then mixture was concentrated in vacuo. The residue was purifiedby prep-HPLC (0.1% HCl) to give the title compound (1.44 g, 78% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (d, J=8.8 Hz, 2H), 8.07(s, 1H), 7.76 (d, J=8.8 Hz, 2H), 6.80 (t, J=53.2 Hz, 1H), 3.96 (s, 3H);LC-MS (ESI⁺) m/z 330.9 (M+H)⁺.

Step 4—Methyl4-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]benzoate

Methyl 4-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]benzoate (500 mg, 1.51mmol), TEA (382 mg, 3.78 mmol), acetonitrile-dichloropalladium (58.8 mg,227 umol), dicyclohexyl-[2-(2,6-dimethoxy phenyl)phenyl]phosphane (93.0mg, 227 umol) and HBPin (1.93 g, 15.1 mmol) were taken up into amicrowave tube in toluene (10 mL). The sealed tube was heated at 90° C.for 60 minutes under microwave. On completion, the mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified bysilica gel chromatography to give the title compound (440 mg, 54% yield)as a yellow solid. LC-MS (ESI⁺) m/z 379.2 (M+H)⁺.

4-[4-[5-[[(1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]-3-(difluoromethyl)pyrazol-1-yl]benzoicAcid (Intermediate EC)

Step 1—Methyl4-[4-[5-[[(1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]-3-(difluoromethyl)pyrazol-1-yl]benzoate

To a solution of methyl4-[3-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]benzoate(379 mg, 702 umol, Intermediate EB) and tert-butylN-[(1S,2R)-2-[(2-bromopyrazolo[1,5-a]pyrimidin-5-yl)amino]cyclohexyl]carbamate(160 mg, 390 umol, Intermediate EA) in a mixed solvent of H₂O (0.6 mL)and dioxane (3 mL) was added K₂CO₃ (162 mg, 1.17 mmol) and XPHOS-PD-G₂(30.7 mg, 39.0 umol). The reaction mixture was stirred at 90° C. for 17hours. On completion, the mixture was concentrated in vacuo to removethe solvent dioxane. The residue was purified by reverse phasechromatography (0.1% HCl) to give the title compound (80.0 mg, 35%yield) as a yellow solid. LC-MS (ESI⁺) m/z 582.1 (M+H)⁺.

Step2—4-[4-[5-[[(1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]-3-(difluoromethyl)pyrazol-1-yl]benzoicacid

To a solution of methyl4-[4-[5-[[(1R,2S)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]pyrazolo[1,5-a]pyrimidin-2-yl]-3-(difluoromethyl)pyrazol-1-yl]benzoate (80.0 mg,138 umol) in a mixed solvent of THF (2 mL) and H₂O (0.4 mL) was addedLiOH (16.5 mg, 688 umol). The reaction mixture was stirred at rt for 17hours. On completion, the mixture was acidified with 1N HCl solutionuntil the pH=6-7, then concentrated in vacuo to give the title compound(75.0 mg, 96% yield) as a yellow solid. LC-MS (ESI⁺) m/z 568.3 (M+H)⁺.

2-(4-Pyridyl)oxazole-4-carboxylic Acid (Intermediate ED)

Step 1—Ethyl 2-(4-pyridyl)oxazole-4-carboxylate

To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(1.50 g, 7.31 mmol) and ethyl 2-bromooxazole-4-carboxylate (1.61 g, 7.31mmol, CAS #460081-20-3) in a mixed solvent of dioxane (20 mL) and H₂O (4mL) was added Cs₂CO₃ (7.15 g, 21.9 mmol) and Pd(dppf)Cl₂ (267 mg, 365umol) under nitrogen atmosphere. The reaction mixture was stirred at 80°C. for 16 hours. On completion, the reaction mixture was filtered andthe filtrate was concentrated in vacuo to give a residue. The residuewas purified by column chromatography (Petroleum ether/Ethylacetate=1/1, PE/EA=1/1) to give the title compound (200 mg, 12% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.82-8.77 (m, 2H), 8.37 (s,1H), 8.01-7.97 (m, 2H), 4.47 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).

Step 2—2-(4-Pyridyl)oxazole-4-carboxylic Acid

To a solution of ethyl 2-(4-pyridyl)oxazole-4-carboxylate (0.2 g, 916umol) in THF (5 mL), MeOH (1 mL) and H₂O (1 mL) was added LiOH (26.34mg, 1.10 mmol). The reaction mixture was stirred at rt for 12 hours. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was then diluted with H₂O and the aqueous phase was acidifiedwith conc. HCl until the pH=6. The mixture was concentrated in vacuo togive the title compound (220 mg) as a yellow solid.

4-[3-Carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid (Intermediate EE)

Step 1—Methyl4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

To a solution of 2-(4-pyridyl)oxazole-4-carboxylic acid (200 mg, 1.05mmol, Intermediate ED) and methyl4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate (328 mg, 1.26 mmol,Intermediate CL) in DMF (5 mL) was added DIPEA (679 mg, 5.26 mmol, 915uL). The mixture was stirred at rt for 12 minutes, and then HATU (479mg, 1.26 mmol) was added. The reaction mixture was stirred at rt for 12hours. On completion, the mixture was diluted with H₂O (10 mL) andextracted with EA (2×20 mL). The combined organic layers wereconcentrated in vacuo to give the title compound (60.0 mg, 13% yield) asa brown solid. LC-MS (ESI⁺) m/z 433.2 (M+H)⁺.

Step2—4-[3-Carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid

To a solution of methyl4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate(60.0 mg, 138 umol) in THF (8 mL) and H₂O (2 mL) was added LiOH (4.99mg, 208 umol). The reaction mixture was stirred at rt for 12 hours. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was then diluted with H₂O and the aqueous phase was acidifiedwith conc. HCl until the pH=6. The reaction mixture was concentrated invacuo to give a residue. The residue was purified by reverse phasechromatography (0.1% HCl) to give the title compound (25.0 mg, 43%yield) as a white solid. LC-MS (ESI⁺) m/z 419.1 (M+H)⁺.

Tert-Butyl N-[3-(3-aminopropoxy)propyl]carbamate (Intermediate EF)

To a mixture of 3-(3-aminopropoxy)propan-1-amine (499 mg, 3.78 mmol, CAS#2157-24-6) in CHCl₃ (25 mL) was added a solution of tert-butoxycarbonyltert-butyl carbonate (165 mg, 756 umol) in CHCl₃ (5 mL) dropwise. Thenthe reaction mixture was stirred at rt for 16 hours. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (DCM:MeOH=10:1) to givethe title compound (140 mg, 79% yield) as a light yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 4.87 (s, 1H), 3.42 (q, J=6.4 Hz, 4H), 3.15 (q, J=5.6Hz, 2H), 2.76 (t, J=6.4 Hz, 2H), 1.70-1.63 (m, 4H), 1.37 (s, 9H).

4-(4-(2-(2-((Tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoicAcid (Intermediate EG)

Step 1—Methyl4-(4-(2-(2-((tert-butoxycarbonyl)(cyclopropylmethyll)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoate

To a solution of methyl4-[4-amino-3-(trifluoromethyl)pyrazol-1-yl]benzoate (300 mg, 1.05 mmol,synthesized via Steps 1-3 of Intermediate DE) and2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (378 mg, 1.05 mmol, synthesized via Steps 1-4 of Intermediate DF)in DMF (5 mL) was added DIPEA (408 mg, 3.16 mmol). Then, HATU (478 mg,1.26 mmol) was added and the reaction mixture was stirred at rt for 0.5hour. On completion, the reaction mixture was quenched with water (20mL) and filtered. The filtered cake was collected and dried in vacuo togive the title compound (659 mg, 100% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.99 (s, 1H), 8.55 (d, J=5.2 Hz, 1H),8.44 (s, 1H), 8.38 (s, 1H), 8.21 (d, J=8.8 Hz, 2H), 7.89 (d, J=8.8 Hz,2H), 7.65 (dd, J=1.2, 5.2 Hz, 1H), 4.01-3.95 (m, 5H), 1.60 (s, 9H),1.30-1.20 (m, 1H), 0.50-0.43 (m, 2H), 0.30 (m, 2H); LC-MS (ESI⁺) m/z627.1 (M+H)⁺.

Step2—4-(4-(2-(2-((Tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(trifluoromethyll)-1H-pyrazol-1-yl)benzoicAcid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]-oxazole-4-carbonyl]amino]-3-(trifluoromethyl)pyrazol-1-yl]benzoate(659 mg, 1.05 mmol) in a mixed of solvent THF (30 mL), H₂O (10 mL) andmethanol (10 mL) was added LiOH (126 mg, 5.26 mmol). The reactionmixture was stirred at rt for 12 hours. On completion, the reactionmixture was concentrated in vacuo. The residue was diluted with water(20 mL) and acidified with 1N HCl until the pH=4, then the mixture wasfiltered. The filtered cake was collected and dried in vacuo to give thetitle compound (700 mg, 91% yield) as a white solid. LC-MS (ESI⁺) m/z613.0 (M+H)⁺.

[3-[4-Amino-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol(Intermediate EH)

Step 1—[3-[4-Nitro-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol

To a solution of 4-nitro-3-(trifluoromethyl)-1H-pyrazole (10.0 g, 55.2mmol, synthesized via Step 1 of Intermediate DE) and [3-(hydroxymethyl)phenyl]boronic acid (12.9 g, 85.3 mmol) in DCM (200 mL) was addedCu(OAc)₂ (15.0 g, 82.8 mmol) and pyridine (17.4 g, 220 mmol). Themixture was stirred at rt for 16 hours under oxygen (15 psi pressure).On completion, the mixture was concentrated in vacuo. The mixture waspurified by silica gel column (PE:EA=1:1) to give the title compound(8.00 g, 50% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.90(s, 1H), 7.93 (s, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H),7.48 (d, J=7.6 Hz, 1H), 5.45 (t, J=6.0 Hz, 1H), 4.62 (d, J=6.0 Hz, 2H).

Step 2—[3-[4-Amino-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol

To a solution of[3-[4-nitro-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol (1.00 g,3.48 mmol) in MeOH (20.0 mL) was added Pd/C (200 mg, 10 wt %) underhydrogen (15 psi pressure). The mixture was stirred at rt for 3 hours.On completion, the mixture was filtered and concentrated in vacuo. Themixture was purified by silica gel column (PE:EA=1:1) to give the titlecompound (700 mg, 78% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.60 (s, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.24(d, J=7.2 Hz, 1H), 4.70 (d, J=3.2 Hz, 2H), 3.28 (s, 2H), 1.76 (s, 1H).

Tert-ButylN-(cycloproylmethyl)-N-[4-[4-[[1-[3-(hydroxymethyl)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (IntermediateEI)

To a solution of[3-[4-amino-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methanol (400 mg,1.56 mmol, Intermediate EH) and2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (558 mg, 1.56 mmol, Intermediate OM) in DMF (5.00 mL) was addedHATU (709 mg, 1.87 mmol) and DIPEA (602 mg, 4.67 mmol). The mixture wasstirred at rt for 30 minutes. On completion, the mixture was quenchedwith H₂O (1 mL) and concentrated in vacuo. The mixture was purified byreverse phase prep-HPLC (0.1% FA) to give the title compound (320 mg,34% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 9.08 (s, 1H),8.92 (s, 1H), 8.55 (d, J=5.2 Hz, 1H), 8.44 (s, 1H), 8.38 (s, 1H), 7.83(s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.66 (dd, J=1.2, 5.2 Hz, 1H), 7.52 (t,J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 4.83 (d, J=5.2 Hz, 2H), 3.97 (d,J=7.2 Hz, 2H), 1.90-1.82 (m, 1H), 1.59 (s, 9H), 1.28-1.25 (m, 1H),0.49-0.43 (m, 2H), 0.33-0.29 (m, 2H).

4-[2-[2-[2-(Aminomethyl)morpholin-4-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate EJ)

Step 1—Tert-ButylN-[[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate

To a solution of2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethanesulfonate (195 mg, 443 umol, synthesized via Steps 1-2 of Example184) and tert-butyl N-(morpholin-2-ylmethyl)carbamate (287.92 mg, 1.33mmol, CAS #173341-02-1) in CH₃CN (30 mL) was added NaHCO₃ (111 mg, 1.33mmol, 51.7 uL). The mixture was stirred at 80° C. for 6 hours. Oncompletion the mixture was concentrated and extracted with EA (3×30 mL).The combined organic layers were washed with brine (50 mL, dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Themixture was purified by column chromatography (TLC; PE:EA 1:1) to givethe title compound (100 mg, 35% yield) as a yellow oil. LC-MS (ESI⁺) m/z560.2 (M+H)⁺.

Step2—4-[2-[2-[2-(Aminomethyl)morpholin-4-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate (50.0 mg, 89.3 umol) in DCM(2 mL) was added HCl in dioxane (4 M, 1 mL). The mixture was stirred atrt for 0.5 hr. On completion, the mixture was concentrated in vacuo togive the title compound (44.3 mg, HCl salt, 90% yield) as a yellow oil.LC-MS (ESI⁺) m/z 460.2 (M+H)⁺.

Tert-Butyl N-(5-oxopentyl)carbamate (Intermediate EK)

To a solution of oxalyl dichloride (312 mg, 2.46 mmol, 215 uL) indichloromethane (5 mL) at −78° C. was added dimethyl sulfoxide (384 mg,4.92 mmol, 384 uL) dissolved in dichloromethane (0.5 mL) dropwise, whilekeeping the temperature below −65° C. Five minutes later, tert-butylN-(5-hydroxypentyl)carbamate (500 mg, 2.46 mmol, 500 uL, CAS #:75178-90-4) dissolved in dichloromethane (0.5 mL) was added slowly tothe solution and the mixture was stirred at −78° C. for 15 min. Finally,triethylamine (1.24 g, 12.3 mmol, 1.71 mL) was added dropwise andstirred the reaction was stirred for 15 min. The mixture was allowed towarm to rt and stirred for 1 hour. The reaction mixture was quenchedwith water (10 mL), and extracted with dichloromethane (3×5 mL). Thecombined organic layers were washed with brine (2×10 mL), dried oversodium sulfate, filtered and concentrated in vacuo to give titlecompound (450 mg, crude) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ6.76-6.60 (m, 1H), 4.96-4.74 (m, 1H), 3.13-3.02 (m, 1H), 2.00-1.93 (m,2H), 1.76-1.68 (m, 2H), 1.43 (s, 9H), 1.20 (t, J=7.2 Hz, 1H).

4-[2-(5-Aminopentylamino)ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate EL)

Step 1—Tert-ButylN-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]pentyl]carbamate

To a solution of4-(2-aminoethylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(100 mg, 283 umol, HCl, Intermediate DJ) and tert-butylN-(5-oxopentyl)carbamate (68.5 mg, 340 umol, Intermediate EK) in THF (20mL) was added KOAc (55.6 mg, 567 umol). The mixture was stirred at rtfor 30 minutes, then NaBH(OAc)₃ (150 mg, 709 umol) was added inportions. The mixture was stirred at rt for 11.5 hours. The reactionmixture was quenched with water (1 mL) and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (Petroleumether/Ethyl acetate=5/1 to dichloromethane:methanol=10/1) to give titlecompound (60.0 mg, 39% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆)δ 11.11 (s, 1H), 9.07 (s, 2H), 7.65-7.60 (m, 1H), 7.31 (d, J=8.8 Hz,1H), 7.10 (d, J=6.8 Hz, 1H), 6.87 (t, J=6.8 Hz, 1H), 5.08 (dd, J=5.2,12.8 Hz, 1H), 3.77-3.67 (m, 2H), 3.14-3.04 (m, 2H), 2.97-2.85 (m, 3H),2.81-2.72 (m, 2H), 2.64-2.56 (m, 2H), 2.10-1.98 (m, 1H), 1.68-1.61 (m,2H), 1.59-1.53 (m, 2H), 1.45-1.34 (m, 2H).

Step2—4-[2-(5-Aminopentylamino)ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

Tert-butylN-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]pentyl]carbamate (60.0 mg, 119 umol, HCl) was dissolved in 4 M HClin dioxane (5 mL). The mixture was stirred at rt for 1 hour. Thereaction mixture was then concentrated in vacuo to give title compound(60.0 mg, 95% yield) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10(s, 1H), 9.10 (s, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H),7.10 (d, J=7.2 Hz, 1H), 6.86 (s, 1H), 5.07 (dd, J=5.2, 12.4 Hz, 1H),3.98-3.86 (m, 1H), 3.51-3.41 (m, 4H), 3.36-3.29 (m, 1H), 3.11-3.03 (m,2H), 2.96-2.86 (m, 3H), 2.76-2.73 (m, 2H), 2.69-2.59 (m, 2H), 2.07-1.99(m, 1H), 1.70-1.53 (m, 4H), 1.43-1.33 (m, 2H).

(2R)-2-hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide(Intermediate EM)

To a mixture of tert-butyl4-[4-[[(8R)-8-[(2R)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazine-1-carboxylate(0.09 g, 164 umol, synthesized via Steps 1-14 of Intermediate DR) in DCM(2 mL) was added HCl in dioxane (4.0 M, 6.43 mL). Then the reactionmixture was stirred at rt for 20 minutes. On completion, the reactionmixture was concentrated in vacuo to give the title compound (79.5 mg,100% yield) as white solid. LC-MS (ESI⁺) m/z 446.1 (M+H)⁺.

2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oic acid(Intermediate EN)

Step 1—Tert-Butyl(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate

To a stirred solution of 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethan-1-ol(1.0 g, 5.2 mmol, CAS #86770-74-3) and KOH (0.32 g, 5.6 mmol) in 1,4dioxane (4 mL) and water (8 mL) was added Boc-anhydride (1.24 g, 5.6mmol) dropwise at 10° C. The resulting reaction mixture was allowed towarm to rt and stirred for 16 h. The reaction mixture was transferredinto ice water and the resulting mixture was extracted using ethylacetate (3×100 mL). The combined organic layers were dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to afford crude product. The crude product was purifiedusing silica gel column chromatography (8% MeOH-DCM) to give tert-butyl(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate as a colorlessoil (1.2 g, 79%). LC-MS (ESI⁺) m/z 293.13 (M+H)⁺.

Step 2—2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oicAcid

To a stirred solution of tert-butyl(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (0.38 g, 1.29mmol) and 2-bromoacetic acid (0.54 g, 3.8 mmol) in toluene:THF (1:1, 4mL) was added NaOH (0.31 g, 7.7 mmol) at 45° C. The resulting reactionmixture stirred at 45° C. for 16 h. The reaction mixture was thenevaporated, water (10 mL) was added and aqueous layer was acidified with1 N HCl solution. The resulting mixture was extracted using DCM (3×50mL) and the combined organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureto give 2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oicacid as a colorless oil (0.24 g, 53%). LC-MS (ESI⁺) m/z 351.4 (M+H)⁺.

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(piperidin-4-yl)nicotinamideHydrochloride (Intermediate EO)

Step 1—Tert-Butyl4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)piperidine-1-carboxylate

A solution of6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinic acid (0.5g, 1.56 mmol, Intermediate N), tert-butyl4-aminopiperidine-1-carboxylate (0.32 g, 1.56 mmol, CAS #87120-72-7),PyBOP (1.22 g, 2.34 mmol) and DIPEA (0.4 mL, 2.34 mmol) in DMF (3 mL)was stirred at rt for 2 h. On completion, the reaction mixture wastransferred into ice water and the resulting mixture was extracted usingethyl acetate (3×30 mL). The combined organic layers were dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to afford crude product. The crude product was purifiedusing silica gel column chromatography (5% MeOH-DCM) to give tert-butyl4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)piperidine-1-carboxylateas a yellow solid (0.6 g, 76%). LC-MS (ESI⁺) m/z 504.50 (M+H)⁺.

Step2—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(piperidin-4-yl)nicotinamideHydrochloride

To the solution tert-butyl4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)piperidine-1-carboxylate (0.6 g, 1.19 mmol) in DCM (10 mL) wasadded 4N HCl in dioxane (3 mL) at 0° C. Then the reaction mixture wasallowed to warm to rt and stirred for 3 h. The reaction mixture wasevaporated under reduced pressure to afford the crude product. The crudeproduct was triturated using MTBE to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(piperidin-4-yl)nicotinamidehydrochloride as a white solid (0.45 g, 85%). LC-MS (ESI⁺) m/z 404.40(M+H)⁺.

Tert-Butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)(methyl)carbamate(Intermediate EP)

Step 1—2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate

To a stirred solution of 2,2′-(ethane-1,2-diylbis(oxy))bis(ethan-1-ol)(15.0 g, 0.10 mmol, CAS #112-27-6), silver oxide (34.65 g, 34.65 mmol),and sodium iodide (16.5 g, 1.1 mmol) in DCM (200 mL) was added tosylchloride (19.06 g, 0.10 mmol) portion-wise at 0° C., and the reactionmixture was stirred for 3 h. On completion, the reaction mixture wasfiltered through a pad of celite and the filtrate was extracted usingDCM (3×20 mL). The combined organic layer was washed with water, driedover anhydrous sodium sulfate and filtered. The filtrate was evaporatedunder reduced pressure to get the crude product. The crude product waspurified using silica gel column chromatography (3% MeOH:DCM) to give2-(2-(2-hydroxyethoxy)ethoxy)ethyl 4-methylbenzenesulfonate as a yellowliquid (18 g, 59%). LC-MS (ESI⁺) m/z 305.34 (M+H)⁺.

Step 2—2-(2-(2-(methylamino)ethoxy)ethoxy)ethan-1-ol

To a stirred solution of 2-(2-(2-hydroxyethoxy)ethoxy)ethyl4-methylbenzenesulfonate (5.0 g, 16.4 mmol) in THF (15 mL) was added 2MMethylamine in THF (34 mL, 66 mmol) at rt, then the reaction mixture washeated to 90° C. and stirred for 8 h. The reaction mixture was thenfiltered and filtrate was evaporated under reduce pressure to give2-(2-(2-(methylamino)ethoxy)ethoxy)ethan-1-ol as a yellow oil (2.5 g,93% yield). LC-MS (ESI⁺) m/z 164.21 (M+H)⁺.

Step 3—Tert-Butyl (2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamate

To a stirred solution of 2-(2-(2-(methylamino)ethoxy)ethoxy)ethan-1-ol(2.5 g, 15.3 mmol) in DCM (40 mL) was added boc anhydride (20 g, 92mmol) and TEA (4.0 mL, 30.6 mmol) at 0° C. and the reaction mixture wasstirred for 2 h. The reaction mixture was then transferred into icewater and the resulting mixture was extracted with DCM (3×100 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to affordcrude product. The crude product was purified using silica gel columnchromatography (40% EtOAc-Hexane) to give tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamate as a yellowsemisolid (2.2 g, 54%). LC-MS (ESI⁺) m/z 264.32 (M+H)⁺.

Step 4—2,2,5-trimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-ylMethanesulfonate

To a stirred solution oftert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)(methyl)carbamate (2.2 g,8.4 mmol) and triethylamine (3.5 g, 25.08 mmol) in DCM (15 mL) was addedmesyl chloride (1.2 mL, 12.54 mmol) at 0° C., then the reaction mixturewas stirred for 2 h. The reaction mixture was then transferred into icewater and the resulting mixture was extracted with DCM (3×25 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to give2,2,5-trimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl methanesulfonateas a yellow semisolid (2.8 g, 78%).

Step 5—Tert-Butyl (2-(2-(2-azidoethoxy)ethoxy)ethyl)(methyl)carbamate

To a stirred solution of2,2,5-trimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl methanesulfonate(2.8 g, 8.2 mmol) in DMF (10 mL) was added sodium azide (0.8 g, 12.3mmol) at rt. Then the reaction mixture was heated to 60° C. and stirredfor 3 h. The reaction mixture was then transferred into ice water andthe resulting mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to affordcrude product. The crude product was purified using silica gel columnchromatography (30% EtOAc-Hexane) to give tert-butyl(2-(2-(2-azidoethoxy)ethoxy)ethyl)(methyl)carbamate as a yellowsemisolid (1.6 g, 98%). LC-MS (ESI⁺) m/z 355.33 (M+FA adduct)⁺.

Step 6—Tert-Butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)(methyl)carbamate

To a stirred solution of tert-butyl(2-(2-(2-azidoethoxy)ethoxy)ethyl)(methyl)carbamate (1.6 g, 5.6 mmol) in EtOH (15 mL) in anautoclave was added 10% Pd/C (50% wet) (1.6 g) under hydrogen gas (5kg/cm² pressure) at rt for 3 h. The reaction mixture was filteredthrough celite and concentrated under reduced pressure to givetert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)(methyl)carbamate a ascolorless oil (1 g, 68% yield). LC-MS (ESI⁺) m/z 263.32 (M+H)⁺

2-(2-(benzyloxy)ethoxy)ethyl Methanesulfonate (Intermediate EO)

To a stirred solution of 2-(2-(benzyloxy)ethoxy)ethan-1-ol (0.5 g, 2.5mmol, CAS #2050-25-1) and TEA (1.1 mL, 7.6 mmol) in DCM (10 mL) wasadded mesyl chloride (0.3 mL, 3.8 mmol) dropwise at 0° C. The resultingreaction mixture stirred at 0° C. for 2 h. The reaction mixture wastransferred into ice water and the resulting mixture was extracted withDCM (3×50 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure to give 2-(2-(benzyloxy)ethoxy)ethyl methanesulfonate as acolorless oil (0.45 g, 64%).

Tert-Butyl(2-(2-aminoethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate(Intermediate ER)

Step 1—Tert-Butyl(1-phenyl-2,5,11,14-tetraoxa-8-azahexadecan-16-yl)carbamate

To a stirred solution of tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (3.0 g, 12.1 mmol. CAS#153086-78-3, Supplier: Chem-Impex) and 2-(2-(benzyloxy)ethoxy)ethylmethanesulfonate (5.0 g, 18.2 mmol, Intermediate EQ) in DMF (45 mL) wasadded K₂CO₃ (5 g, 36.2 mmol) at rt. The resulting reaction mixtureheated to 80° C. and stirred for 5 h. The reaction mixture wastransferred into ice water and the resulting mixture was extracted usingethyl acetate (3×100 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to afford crude product. The crude product was purifiedusing silica gel column chromatography (5% MeOH-DCM) to give tert-butyl(1-phenyl-2,5,11,14-tetraoxa-8-azahexadecan-16-yl)carbamate as a yellowoil (2.4 g, 47%). LCMS (ESI⁺) m/z 426.55 (M+H)⁺.

Step 2—Tert-Butyl(2-(2-(benzyloxy)ethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate

To a stirred solution of tert-butyl(1-phenyl-2,5,11,14-tetraoxa-8-azahexadecan-16-yl)carbamate (2.4 g, 5.6mmol) and TEA (1.6 mL, 11.2 mmol) in THF (40 mL) was added Boc anhydride(1.47 g, 6.7 mmol) dropwise at 0° C. The resulting reaction mixturestirred at rt for 1 h. The reaction mixture was transferred into icewater and the resulting mixture was extracted using ethyl acetate (3×50mL). The combined organic layer was dried over anhydrous sodium sulfateand filtered. The filtrate was evaporated under reduced pressure to givetert-butyl(2-(2-(benzyloxy)ethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamateas a colorless oil (2.9 g, 98%). LCMS (ESI⁺) m/z 526.67 (M+H)⁺.

Step 3—Tert-Butyl(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)(2-(2-hydroxyethoxy)ethyl)carbamate

To a stirred solution of tert-butyl(2-(2-(benzyloxy)ethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate(3.2 g, 6.1 mmol) in ethanol (60 mL) and acetic acid (0.1 mL) inautoclave was added 10% Pd/C (50% wet) (3.2 g) at rt under nitrogenatmosphere. The resulting reaction mixture stirred under hydrogen gas (2kg/cm² pressure) in autoclave at rt for 4 h. The reaction mixture wasfiltered through a pad of celite and washed with MeOH (50 mL). Thefiltrate was evaporated under reduced pressure to give tert-butyl(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)(2-(2-hydroxyethoxy)ethyl)carbamateas a yellow oil (2.4 g, 81%). LC-MS (ESI⁺) m/z 436.55 (M+H)⁺.

Step4—14-(tert-butoxycarbonyl)-2,2-dimethyl-4-oxo-3,8,11,17-tetraoxa-5,14-diazanonadecan-19-ylmethanesulfonate

To a stirred solution of tert-butyl(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)(2-(2-hydroxyethoxy)ethyl)carbamate(2.2 g, 5.0 mmol) and TEA (2.1 mL, 15.1 mmol) in dichloromethane (50 mL)was added mesyl chloride (0.6 mL, 7.7 mmol) dropwise at 0° C. Theresulting reaction mixture allowed to warm to rt and stirred for 4 h.The reaction mixture was transferred into ice water and the resultingmixture was extracted with DCM (3×100 mL). The combined organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure to give14-(tert-butoxycarbonyl)-2,2-dimethyl-4-oxo-3,8,11,17-tetraoxa-5,14-diazanonadecan-19-ylmethanesulfonate as a brown oil (2.5 g, 96%). LCMS (ESI⁺) m/z 514.63(M+H)⁺.

Step 5—Tert-Butyl(2-(2-azidoethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate

To a stirred solution of14-(tert-butoxycarbonyl)-2,2-dimethyl-4-oxo-3,8,11,17-tetraoxa-5,14-diazanonadecan-19-ylmethanesulfonate (2.5 g, 4.8 mmol) in DMF (25 mL) was added sodium azide(0.48 g, 7.2 mmol) at rt. The resulting reaction mixture was heated to65° C. and stirred for 4 h. The reaction mixture was transferred intoice water and the resulting mixture was extracted with ethyl acetate(3×100 mL). The combined organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureto afford crude product. The crude product was purified using silica gelcolumn chromatography (1% MeOH-DCM) to give tert-butyl(2-(2-azidoethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamateas a yellow liquid (2 g, 89%). LCMS (ESI⁺) m/z 461.56 (M+H)⁺.

Step 6—Tert-Butyl(2-(2-aminoethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate

To a stirred solution of tert-butyl(2-(2-azidoethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamate(1.8 g, 3.9 mmol) in ethanol (100 mL) was added 10% Pd/C (50% wet) (1.8g) at rt under nitrogen atmosphere. The resulting reaction mixture wasstirred under hydrogen gas (2 kg/cm² pressure) in an autoclave at rt for4 h. The reaction mixture was filtered through a pad of celite andwashed with MeOH (50 mL). The filtrate was evaporated under reducedpressure to give tert-butyl(2-(2-aminoethoxy)ethyl)(2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)carbamateas a colorless oil (1.4 g, 82%). LC-MS (ESI⁺) m/z 435.56 (M+H)⁺.

Tert-Butyl((1R,3R)-3-(16-amino-2,5,8,11,14-pentaoxahexadecyl)cyclobutyl)carbamate(Intermediate ES)

Step 1—Tert-Butyl ((1R,3R)-3-(18-phenyl-2,5,8,11,14,17-hexaoxaoctadecyl)cyclobutyl) Carbamate

To a stirred solution of((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methylmethanesulfonate (2.9 g, 10.4 mmol, synthesized via Steps 1-3 ofIntermediate H) and 1-phenyl-2,5,8,11,14-pentaoxahexadecan-16-ol (6.8 g,20.78 mmol, synthesized via Step 1 of Intermediate X) in toluene (30 mL)and 8 N NaOH solution (30 mL) was added TBAB (500 mg, 2.1 mmol) at rt.The resulting reaction mixture then heated to 90° C. and stirred for 16h. The reaction mixture was then transferred into ice water and theresulting mixture was extracted with ethyl acetate (3×100 mL). Thecombined organic layer was dried over anhydrous sodium sulfate andfiltered. The filtrate was evaporated under reduced pressure to affordcrude product. The crude product was purified using silica gel columnchromatography (1% MeOH-DCM) to give tert-butyl((1R,3R)-3-(18-phenyl-2,5,8,11,14,17-hexaoxaoctadecyl)cyclobutyl)carbamateas a colorless oil (2.4 g, 46%). LCMS (ESI⁺) m/z 511.66 (M+H₂O)⁺.

Step 2—Tert-Butyl ((1R,3R)-3-(16-hydroxy-2,5,8,11,14-pentaoxahexadecyl)cyclobutyl)carbamate

To a stirred solution of tert-butyl((1r,3r)-3-(18-phenyl-2,5,8,11,14,17-hexaoxaoctadecyl) cyclobutyl)carbamate (3.15 g, 6.16 mmol) in ethanol (40 mL) and acetic acid (0.3mL) was added 10% Pd/C (50% wet) (3.15 g) at rt under nitrogenatmosphere. The resulting reaction mixture was stirred under hydrogengas (2 kg/cm² pressure) in autoclave at rt for 4 h. The reaction mixturewas filtered through a pad of celite and washed with MeOH (50 mL). Thefiltrate was evaporated under reduced pressure to give tert-butyl((1R,3R)-3-(16-hydroxy-2,5,8,11,14-pentaoxahexadecyl)cyclobutyl)carbamateas a brown oil (2.1 g, 81%). LC-MS (ESI⁺) m/z 421.53 (M+H)⁺.

Step3—1-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)-2,5,8,11,14-pentaoxahexadecan-16-ylmethanesulfonate

To a stirred solution of tert-butyl((1R,3R)-3-(16-hydroxy-2,5,8,11,14-pentaoxahexadecyl) cyclobutyl)carbamate (2.1 g, 5.0 mmol) and TEA (2.1 mL, 15.0 mmol) indichloromethane (50 mL) was added mesyl chloride (0.58 mL, 7.5 mmol)dropwise at 0° C. The resulting reaction mixture stirred at rt for 3 h.The reaction mixture was then transferred into ice water and theresulting mixture was extracted with DCM (3×100 mL). The combinedorganic layer was dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure to give1-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)-2,5,8,11,14-pentaoxahexadecan-16-ylmethanesulfonate as a brown oil (2.3 g, 92%). LCMS (ESI⁺) m/z 499.62(M+H)⁺.

Step 4—Tert-Butyl((1R,3R)-3-(16-azido-2,5,8,11,14-pentaoxahexadecyl)cyclobutyl)carbamate

To a stirred solution of1-((1R,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)-2,5,8,11,14-pentaoxahexadecan-16-ylmethanesulfonate (2.0 g, 4.0 mmol) in DMF (20 mL) was added sodium azide(390 mg, 6.0 mmol) at rt. The resulting reaction mixture then heated to65° C. and stirred for 2 h. The reaction mixture was then transferredinto ice water and the resulting mixture was extracted with ethylacetate (3×100 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure to afford crude product which was purified by silica gel columnchromatography (2% MeOH-DCM) to give tert-butyl((1R,3R)-3-(16-azido-2,5,8,11,14-pentaoxahexadecyl) cyclobutyl)carbamate as a colorless liquid (1.75 g, 98%). LCMS (ESI⁺) m/z 446.55(M+H)⁺.

Step 5—Tert-Butyl((1R,3R)-3-(16-amino-2,5,8,11,14-pentaoxahexadecyl)cyclobutyl)carbamate

To a stirred solution of tert-butyl((1R,3R)-3-(16-azido-2,5,8,11,14-pentaoxahexadecyl) cyclobutyl)carbamate (1.8 g, 4.0 mmol) in ethanol (40 mL) was added 10% Pd/C (50%wet) (1.8 g) at rt under nitrogen atmosphere. The resulting reactionmixture was then stirred under hydrogen gas (2 kg/cm² pressure) inautoclave at rt for 2 h. The reaction mixture was filtered through a padof celite and washed with MeOH (50 mL). The filtrate was evaporatedunder reduced pressure to give tert-butyl((1r,3r)-3-(16-amino-2,5,8,11,14-pentaoxahexadecyl) cyclobutyl)carbamateas a brown oil (1.41 g, 83%). LC-MS (ESI⁺) m/z 420.55 (M+H)⁺

4-(3-carbamoyl-4-(2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)benzoicAcid (Intermediate ET)

Prepared a 5:4:1 mixture of DCM:TFA:H₂O by combining DCM (5.6 mL),trifluoroacetic acid (4.5 mL), and water (1.1 mL). To this solution wasadded Intermediate CN (870 mg, 1.69 mmol) and the reaction mixture wasstirred for 2.5 h at rt. On completion, the solvent was removed and theresidue was placed under high vacuum to yield 1.07 g (quantitativeyield) of the title compound as a brown solid. LC-MS (ESI⁺) m/z 516.1(M+H)⁺.

2-(4-iodobutyl)isoindoline-1,3-dione (Intermediate EU)

Step 1—2-(4-hydroxybutyl)isoindoline-1,3-dione

To a suspension of 4-aminobutan-1-ol (5.05 g, 48.95 mmol) in toluene(200 mL) was added phthalic anhydride (7.25 g, 48.95 mmol). The reactionmixture was stirred under a Dean-Stark apparatus at 110° C. for 16 h at.The reaction mixture was then cooled to rt and washed with a 1N aqueoussolution of HCl. The organics were washed with brine, dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography (gradient of 25-75% EthylAcetate in Hexanes) to yield the title compound (8.62 g, 76%) as acolorless oil.

Step 2—4-(1,3-dioxoisoindolin-2-yl)butyl Methanesulfonate

2-(4-hydroxybutyl)isoindoline-1,3-dione (7.6 g, 32.6 mmol) was dissolvedin dichloromethane (200 mL) and cooled to 0° C. Triethylamine (5.9 mL,42.4 mmol) and methane sulfonyl chloride (2.77 mL, 35.83 mmol) wereadded and the reaction was stirred for 1.5 hours. The reaction mixturewas then quenched with a saturated aqueous solution of NaHCO₃, and thelayers were partitioned. The organic layer was washed with a saturatedaqueous solution of NaHCO₃ (3 times), dried over magnesium sulfate,filtered and concentrated in vacuo to give the title compound (9.9 g,97%) as an off-white powder.

Step 3—2-(4-iodobutyl)isoindoline-1,3-dione

4-(1,3-dioxoisoindolin-2-yl)butyl methanesulfonate (9.90 g, 31.82 mmol)was dissolved in acetone (200 mL). Then sodium iodide (14.4 g, 95.5mmol) was added and the reaction mixture was heated to 58° C. for 2hours. The reaction mixture was then concentrated in vacuo, then theresidue was diluted with water and the aqueous layer was extracted withEthyl Acetate (3 times). The combined organic layer was washed withwater, dried over magnesium sulfate, filtered and concentrated in vacuo.The title compound was isolated as a yellow powder (10.22 g, 93%). LC-MS(ESI⁺) m/z 344.0 (M+H)⁺.

5-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)ethoxy)pentan-1-amine(Intermediate EV)

Step 1—2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)ethan-1-ol

To a suspension of NaH (2.9 g, 73.42 mmol, 60% dispersion in mineraloil) in dry DMF (150 mL) was added ethylene glycol (17.2 mL, 306 mmol)dropwise. The reaction mixture was stirred for 30 minutes at rt beforethe addition of potassium iodide (10.15 g, 61.19 mmol) and2-(4-bromobutoxy)tetrahydro-2H-pyran (15.37 g, 61.19 mmol, CAS#31608-22-7). The reaction was stirred at rt for 16 h. The reactionmixture was then quenched with a saturated aqueous solution of NH₄Cl.The aqueous layer was extracted with Ethyl Acetate (3 times). Thecombined organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (gradient of 20-100% Ethyl Acetate in Hexanes). The titlecompound was isolated as a yellow powder (4.33 g, 30% yield).

Step2—2-(5-(2-(4-((tetrahydro-2H-pyran-2-yloxy)butoxy)ethoxy)pentyl)isoindoline-1,3-dione

2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)ethan-1-ol (2.2 g, 9.5 mmol)was dissolved in dry DMF (40 mL). Then NaH (0.41 g, 10.4 mmol, 60%dispersion in mineral oil) was carefully added. After stirring for 30minutes at rt, 2-(4-iodobutyl)isoindoline-1,3-dione (3.9 g, 11.3 mmol,Intermediate EU) was added and the reaction mixture was stirred at rtfor 16 h. The reaction mixture was then was quenched with water and theaqueous layer was extracted with Ethyl Acetate (3 times). The combinedorganic layer was washed with water, dried over magnesium sulfate,filtered and concentrated. The resulting residue was purified by silicagel chromatography (gradient of 0-100% Ethyl Acetate in Hexanes) to givethe title compound (956 mg, 22% yield) as a colorless oil. LC-MS (ESI⁺)m/z 449.2 (M+H)⁺.

Step3—5-(2-(4-((tetrahydro-2H-pyran-2-yloxy)butoxy)ethoxy)pentan-1-amine

2-(5-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)ethoxy)pentyl)isoindoline-1,3-dione(200 mg, 0.44 mmol) was dissolved in methanol (3 mL) and hydrazinehydrate (64 μL, 1.32 mmol) was added. The reaction mixture was heated to70° C. and stirred for 3 hours. The reaction mixture was then cooled tort and concentrated in vacuo. The residue was triturated in diethylether, and the white precipitate was filtered off. The filtrate was thenconcentrated in vacuo to give the title compound as a colorless oil (120mg, 87% yield).

Tert-Butyl (3,6,9,12-tetraoxapentadec-14-yn-1-yl)carbamate (IntermediateEW)

To a solution of tert-butyl(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (10.0 g, 34.1mmol, Step 1 of Intermediate EN) in anhydrous THF (250 mL) was addedsodium hydride (1.63 g, 40.94 mmol, 60% dispersion in mineral oil) inone portion under nitrogen atmosphere. The reaction mixture was stirredat rt for 0.5 h and thereafter it was cooled to 0° C. An 80% solution of3-bromoprop-1-yne in toluene (5.7 mL, 51.2 mmol) was added dropwise tothe reaction mixture at 0° C. over a period of 10 min. The resultingreaction mixture was stirred at 0° C. for 1 h and thereafter it wasallowed to warm to rt. The resulting reaction mixture was stirredovernight at rt. Then the reaction mixture was quenched with a smallaliquot of methanol (1.6 mL) and concentrated on a rotary evaporator.The obtained crude material was suspended in DCM (100 mL) and was washedwith water (2×30 mL) and brine (50 mL). The resulting organic layer wasdried over anhydrous sodium sulphate, filtered and concentrated on arotary evaporator. The obtained crude product was purified by silica gelchromatography (gradient Ethyl acetate/Hexanes) to give the titlecompound (6.25 g, 55%) as a light yellow viscous liquid.

3-Benzyloxy-5-methoxy-aniline (Intermediate EX)

Step 1—3-Methoxy-5-nitro-phenol

A mixture of KOH (11.6 g, 206 mmol) and1-bromo-3-methoxy-5-nitro-benzene (12.0 g, 51.7 mmol) in a mixed solventof dioxane (80 mL) and H₂O (80 mL) was degassed for 5 minutes. ThenPd₂(dba)₃ (473 mg, 517 umol) and tBuXphos (439 mg, 1.03 mmol) were addedto the reaction mixture. The resulting reaction mixture was degassed fora further 0.5 hour, and then the reaction mixture was heated at 100° C.for 12 hours under a nitrogen atmosphere. On completion, the mixture wascooled, then acidified with 5 M HCl until the pH=1.0 and extracted withEtOAc (2×200 mL). The combined organic layer was washed with saturatedbrine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by silica gel chromatography(PE:EA=3:1) to give the title compound (8.60 g, 98% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H), 7.18 (d, J=2.4 Hz,2H), 6.75 (t, J=2.4 Hz, 1H), 3.81 (s, 3H).

Step 2—1-Benzyloxy-3-methoxy-5-nitro-benzene

To a mixture of 3-methoxy-5-nitro-phenol (4.00 g, 23.6 mmol) in acetone(150 mL) was added K₂CO₃ (8.17 g, 59.1 mmol) and BnBr (6.07 g, 35.4mmol, 4.21 mL). Then the reaction mixture was stirred at 50° C. for 12hours. On completion, the reaction mixture was filtered, and thefiltrate was concentrated in vacuo to remove acetone. The residue waswashed with water (100 mL) and extracted with EA (2×200 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (PE:EA=8:1) to give the title compound (6.00g, 97% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.34 (m,7H), 6.84 (t, J=2.4 Hz, 1H), 5.13 (s, 2H), 3.87 (s, 3H).

Step 3—3-Benzyloxy-5-methoxy-aniline

To a solution of 1-benzyloxy-3-methoxy-5-nitro-benzene (2.00 g, 7.71mmol) in MeOH (45 mL) and H₂O (10 mL) was added Fe (4.31 g, 77.1 mmol)followed by NH₄Cl (4.12 g, 77.1 mmol). Then, the reaction mixture wasstirred at 75° C. for 14 hours. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to remove MeOH. Theresidue was washed with water (100 mL) and extracted with EA (2×200 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (1.14 g, 64% yield) asblack brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.28 (m, 5H), 6.04 (t,J=2.0 Hz, 1H), 5.98 (t, J=2.0 Hz, 1H), 5.92 (t, J=2.0. Hz, 1H), 5.03 (s,2H), 3.76 (s, 3H); LC-MS (ESI⁺) m/z 230.1 (M+H)⁺.

2-[2-[2-[2-(Benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylMethanesulfonate (Intermediate EY)

Step 1—Benzyl N-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate

To a solution of 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethanol (6.00 g,31.0 mmol, Intermediate DC) in ACN (50 mL) and H2O (50 mL) was addedCbzCl (6.36 g, 37.2 mmol) and NaHCO₃ (7.83 g, 93.1 mmol). The reactionmixture was stirred at rt for 12 hours. On completion, the reactionmixture was diluted with water (30 mL) and extracted with EA (3×30 mL).The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo to give a residue. The residue waspurified by column chromatography to give the title compound (9.20 g,90% yield) as a colorless oil. LC-MS (ESI⁺) m/z 350.0 (M+Na)⁺.

Step 2—2-[2-[2-[2-(Benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylMethanesulfonate

To a mixture of benzylN-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (1.00 g, 3.05mmol) in dichloromethane (10 mL) was added TEA (617 mg, 0.85 mL, 6.10mmol) and MsCl (524 mg, 0.354 mL, 4.57 mmol) dropwise at 0° C. undernitrogen atmosphere. The reaction mixture then allowed to warm to rt andstirred for 1 hour. On completion, the reaction mixture was poured into5 mL of water and acidified with citric acid until the pH=5-6. Themixture was extracted with dichloromethane (2×10 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (1.10 g, 88% yield) as a light yellowoil. LC-MS (ESI⁺) m/z 406.0 (M+H)⁺.

7-((3-Hydroxy-5-methoxyphenyl)amino)-5-(methylthio)imidazo[1,2-c]pyrimidine-8-carboxamide(Intermediate EZ)

Step1—4-(3-Benzyloxy-5-methoxy-anilino)-6-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile

To a mixture of 3-benzyloxy-5-methoxy-aniline (6.90 g, 30.1 mmol,Intermediate EX) and4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile (6.62 g, 30.1mmol, CAS #33097-13-1) in THE (20 mL) was added DIPEA (5.83 g, 45.1mmol, 7.88 mL) dropwise at 0° C. The reaction mixture was then allowedto warm to rt and stirred for 12 hours. On completion, the reactionmixture was concentrated in vacuo to remove THE. The residue was washedwith water (100 mL) and extracted with EA (2×200 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (9.00 g, 72% yield) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) 6 7.51-7.29 (m, 5H), 6.93 (t, J=2.0 Hz,1H), 6.85 (t, J=2.0 Hz, 1H), 6.45 (t, J=2.4 Hz, 1H), 5.08 (s, 2H), 3.73(s, 3H), 2.46 (s, 3H); LC-MS (ESI⁺) m/z 412.9 (M+H)⁺.

Step2—4-Amino-6-(3-benzyloxy-5-methoxy-anilino)-2-methylsulfanyl-pyrimidine-5-carbonitrile

To a solution4-(3-benzyloxy-5-methoxy-anilino)-6-chloro-2-methylsulfanylpyrimidine-5-carbonitrile(10.2 g, 24.7 mmol) in THF (50 mL) was added NH3·H₂O (30 mL). Thereaction mixture was stirred at 70° C. for 12 hours. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was triturated with DCM (100 mL) and filtered. The filter cakewas collected to afford a white solid. Then, the white solid wastriturated with acetone (50 mL) to give the title compound (7.79 g, 80%yield) as an off-white solid. LC-MS (ESI⁺) m/z 394.0 (M+H)⁺.

Step3—4-Amino-6-(3-benzyloxy-5-methoxy-anilino)-2-methylsulfanyl-pyrimidine-5-carboxamide

To a mixture4-amino-6-(3-benzyloxy-5-methoxy-anilino)-2-methylsulfanylpyrimidine-5-carbonitrile(7.79 g, 19.8 mmol) in DMSO (80 mL) and EtOH (80 mL) was added NaOH (5M, 19.8 mL) and H₂O₂ (11.2 g, 99.0 mmol, 9.51 mL, 30% solution)dropwise. The reaction mixture was stirred at rt of 2.5 hours. Oncompletion, the reaction mixture was quenched by slow addition ofsaturated Na₂S₂O₃ solution (50 mL) under stirring. The reaction mixturewas concentrated in vacuo to remove the EtOH. The residue was pouredinto 100 mL of water and acidified with 1M HCl until the pH=7. Themixture was extracted with EA (2×200 mL). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (10.0 g, 91% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.89 (s, 1H), 7.56 (s, 2H), 7.47-7.31 (m, 5H), 6.91 (t, J=2.0 Hz, 1H),6.88 (t, J=2.0 Hz, 1H), 6.85 (s, 2H), 6.25 (t, J=2.0 Hz, 1H), 5.07 (s,2H), 3.72 (s, 3H), 2.46 (s, 3H); LC-MS (ESI⁺) m/z 412.0 (M+H)⁺.

Step4—7-(3-Benzyloxy-5-methoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide

To a mixture of4-amino-6-(3-benzyloxy-5-methoxy-anilino)-2-methylsulfanylpyrimidine-5-carboxamide(8.00 g, 19.4 mmol) in DMF (50 mL) was added a solution of2-chloroacetaldehyde (11.4 g, 58.3 mmol, 9.39 mL, 40% solution inwater). The reaction mixture was stirred at 60° C. for 8 hours. Oncompletion, the reaction mixture was concentrated in vacuo to remove theDMF. The residue was purified by silica gel chromatography(DCM:MeOH=80:1) to give the title compound (2.30 g, 27% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 12.04 (s, 1H), 10.04 (s, 1H),7.48-7.33 (m, 7H), 6.94-6.92 (m, 1H), 6.88-6.85 (m, 1H), 6.34 (t, J=2.0Hz, 1H), 5.74 (s, 1H), 5.07 (s, 2H), 3.81 (s, 3H), 2.80 (s, 3H); LC-MS(ESI⁺) m/z 436.0 (M+H)⁺.

Step5—7-((3-Hydroxy-5-methoxyphenyl)amino)-5-(methylthio)imidazo[1,2-c]pyrimidine-8-carboxamide

To a solution of7-(3-benzyloxy-5-methoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(2.30 g, 5.28 mmol) in DCM (150 mL) was added a solution of BCl₃ in DCM(1 M, 42.2 mL) under nitrogen atmosphere. The reaction mixture wasstirred at rt for 12 h. On completion, the reaction mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography (dichloromethane:methanol=20:1) to give the titlecompound (1.42 g, 70% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.98 (s, 1H), 7.76 (d, J=1.6 Hz, 1H), 7.55 (d, J=1.6 Hz,1H), 6.67 (d, J=2.0 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 6.10 (d, J=2.0 Hz,1H), 3.71 (s, 3H), 2.80 (s, 3H).

7-(4-Hydroxy-3,5-dimethoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(Intermediate FA)

Step 1—2,6-Dimethoxy-4-Nitro-Phenol

To a solution of 2,6-dimethoxyphenol (5.00 g, 32.4 mmol) in THF (50 mL)was added dropwise tert-butyl nitrite (10.0 g, 97.3 mmol). Then, thereaction mixture was stirred at rt for 0.5 hr. On completion, thereaction mixture was concentrated in vacuo. The residue was purified bycolumn chromatography to give the title compound (3.73 g, 58% yield) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (s, 2H), 6.06 (s, 1H),3.91 (s, 6H).

Step 2—2-Benzyloxy-1,3-dimethoxy-5-nitro-benzene

To a solution of 2,6-dimethoxy-4-nitro-phenol (8.00 g, 40.2 mmol) inacetone (100 mL) was added K₂CO₃ (11.1 g, 80.3 mmol) and KI (667 mg,4.02 mmol) at rt. The suspension was stirred at rt for 1 hr. Then,bromomethylbenzene (10.3 g, 60.3 mmol) was added to the mixturedropwise. The reaction mixture was then heated to 60° C. and stirred for12 hours. On completion, the reaction mixture was concentrated in vacuoto remove the acetone. The residue was diluted with water (100 mL) andextracted with EA (3×150 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography to give thetitle compound (8.62 g, 74% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.51 (s, 2H), 7.45 (d, J=6.8 Hz, 2H), 7.39-7.27 (m, 3H), 5.14(s, 2H), 3.91 (s, 6H).

Step 3—4-Benzyloxy-3,5-dimethoxy-aniline

To a solution of 2-benzyloxy-1,3-dimethoxy-5-nitro-benzene (8.62 g, 29.8mmol) in a mixed solvent of H₂O (50 mL) and EtOH (170 mL) was added Fe(16.6 g, 298 mmol) followed by NH₄Cl (15.9 g, 298 mmol). Then, thereaction mixture was stirred at 75° C. under nitrogen for 1.5 hrs. Oncompletion, the mixture was diluted with MeOH (150 mL), filtered througha pad of Celite and washed with MeOH (80 mL). The filtrate wasconcentrated, and the residue was washed with H₂O (100 mL) and extractedwith EA (2×150 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated in vacuo to give a residue. The residue was purified bycolumn chromatography to give the title compound (7.27 g, 94% yield) asa black brown oil. LC-MS (ESI⁺) m/z 260.0 (M+H)⁺.

Step4—4-(4-Benzyloxy-3,5-dimethoxy-anilino)-6-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile

To a solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbonitrile(6.17 g, 28.0 mmol) and 4-benzyloxy-3,5-dimethoxy-aniline (7.27 g, 28.0mmol) in THF (150 mL) was added DIPEA (5.44 g, 42.1 mmol) dropwise. Thereaction mixture was stirred at rt for 15 hours. On completion, thereaction mixture was diluted with water (150 mL) and filtered. Then, thefilter cake was dried in vacuo to give the title compound (9.49 g, 76%yield) as a yellow solid. LC-MS (ESI⁺) m/z 464.9 (M+Na)⁺.

Step5—4-Amino-6-(4-benzyloxy-3,5-dimethoxy-anilino)-2-methylsulfanyl-pyrimidine-5-carbonitrile

To a mixture of4-(4-benzyloxy-3,5-dimethoxy-anilino)-6-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile(4.49 g, 10.1 mmol) in THF (50 mL) was added NH₃ H2O (7.11 g, 203 mmol).Then, the reaction mixture heated to 70° C. and stirred for 17 hours atautoclave. On completion, the reaction mixture was concentrated in vacuoto give a residue. The residue was triturated with DCM to give the titlecompound (3.74 g, 87% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 7.54-7.48 (m, 2H), 7.41-7.30 (m, 3H), 6.88 (s, 1H), 6.84 (s, 2H), 5.35(s, 2H), 5.02 (s, 2H), 3.85 (s, 6H), 2.50 (s, 3H); LC-MS (ESI⁺) m/z424.0 (M+H)⁺.

Step6—4-Amino-6-(4-benzyloxy-3,5-dimethoxy-anilino)-2-methylsulfanyl-pyrimidine-5-carboxamide

To a solution of4-amino-6-(4-benzyloxy-3,5-dimethoxy-anilino)-2-methylsulfanyl-pyrimidine-5-carbonitrile(5.60 g, 13.2 mmol) in DMSO (30 mL) and EtOH (30 mL) at 0° C. was addedH₂O₂ (7.50 g, 66.1 mmol, 30% solution) and NaOH (5 M, 13.2 mL, 20%solution). The reaction mixture was stirred at rt for 3 hours. Oncompletion, the reaction mixture was quenched with sat.Na₂SO₃. Then themixture was filtered through a pad of celite. After that, the filtercake was washed with H₂O (3×50 mL) and dried to give the title compound(5.70 g, 98% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.82(s, 1H), 7.54 (s, 2H), 7.46 (d, J=6.8 Hz, 2H), 7.41-7.28 (m, 3H), 6.95(s, 2H), 6.83 (s, 2H), 4.85 (s, 2H), 3.76 (s, 6H), 2.45 (s, 3H); LC-MS(ESI⁺) m/z 442.1 (M+H)⁺.

Step7—7-(4-Benzyloxy-3,5-dimethoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide

A mixture of4-amino-6-(4-benzyloxy-3,5-dimethoxy-anilino)-2-methylsulfanyl-pyrimidine-5-carboxamide(5.00 g, 11.3 mmol) and 2-chloroacetaldehyde (3.33 g, 17.0 mmol) in DMF(20 mL) was heated at 60° C. for 6 hours under nitrogen atmosphere. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by column chromatography to give thetitle compound (5.07 g, 96% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 11.88 (s, 1H), 10.00 (s, 1H), 7.42 (d, J=7.2 Hz, 2H), 7.32-7.22(m, 5H), 6.70 (s, 2H), 5.64 (m, 1H), 4.94 (s, 2H), 3.75 (s, 6H), 2.64(s, 3H); LC-MS (ESI⁺) m/z 466.0 (M+H)⁺.

Step8—7-(4-Hydroxy-3,5-dimethoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide

To7-(4-benzyloxy-3,5-dimethoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(1.55 g, 3.33 mmol) was added HBr (22.4 g, 15 mL, 110 mmol, 40%solution). The reaction mixture was stirred at 50° C. for 3 hours undernitrogen atmosphere. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. The residue was triturated withdichloromethane:methanol=10:1 to give the title compound (1.20 g, 96%yield) as a yellow solid. LC-MS (ESI⁺) m/z 376.0 (M+H)⁺.

5,7-Dichloropyrido[4,3-d]pyrimidin-4(3H)-one (Intermediate FB)

Step 1—Tert-ButylN-tert-butoxycarbonyl-N-(2,6-dichloro-4-pyridyl)carbamate

A solution of 2,6-dichloropyridin-4-amine (28.0 g, 172 mmol, CAS#2587-02-2) in THF (400 mL) under nitrogen was cooled to 0° C. with anice-water bath. To this mixture was added a solution of NaHMDS (1 M, 412mL) in THF. After the reaction mixture was stirred at 0° C. for 0.5 h, asolution of (Boc)₂O (82.5 g, 378 mmol, 86.8 mL) in THF (1.2 L) was addedand the ice-water bath was then removed. The reaction mixture was thenstirred at rt for 16 hrs. On completion, the reaction mixture wasquenched with saturated NH₄Cl (1000 mL) and extracted with ethyl acetate(3×500 mL). The combined organic layer was washed with brine (100 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give the title compound (42.0 g, 96% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 8.98 (s, 1H), 8.34 (s, 1H), 1.63 (s, 9H), 1.53 (s,9H).

Step 2—Tert-Butyl4-(tert-butoxycarbonylamino)-2,6-dichloro-pyridine-3-carboxylate

To a solution of LDA (2 M, 169 mL) was added a solution of tert-butylN-tert-butoxycarbonyl-N-(2,6-dichloro-4-pyridyl)carbamate (35.0 g, 96.4mmol) in THF (600 mL) under nitrogen at −78° C. The reaction mixture wasstirred at −78° C. for 0.5 hr. On completion, the reaction mixture wasquenched with saturated NH4Cl, and extracted with ethyl acetate (3×100mL). The combined organic layer was washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE:EA=200:1) to givethe title compound (35.0 g, 100% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.99 (s, 1H), 8.35 (s, 1H), 1.64 (s, 9H), 1.54 (s, 9H).

Step 3—4-Amino-2,6-dichloro-pyridine-3-carboxylic Acid

To a solution of tert-butyl4-(tert-butoxycarbonylamino)-2,6-dichloro-pyridine-3-carboxylate (35 g,96.4 mmol) in DCM (100 mL) was added TFA (139 g, 1.22 mol, 90 mL). Thereaction mixture was stirred at 65° C. for 12 h. On completion, thereaction was mixture was concentrated in vacuo to give the titlecompound (31.0 g, 82% yield, TFA salt) as yellow solid. LCMS (ESI⁺) m/z206.9 (M+H)⁺.

Step 4—4-amino-2,6-dichloro-pyridine-3-carbonyl Chloride

A solution of 4-amino-2,6-dichloro-pyridine-3-carboxylic acid (26.0 g,81.0 mmol, TFA) and SOCl₂ (164 g, 1.38 mol, 100 mL) was heated at 80° C.for 15 min. On completion, the reaction mixture was concentrated invacuo and the title compound was used directly in the next step. LCMS(M+1)⁺: 221.0

Step 5—4-Amino-2,6-dichloro-pyridine-3-carboxamide

To a solution of NH₃/THF (7 M, 50.1 mL) was added a solution of4-amino-2,6-dichloro-pyridine-3-carbonyl chloride (5.30 g, 15.6 mmol,TFA salt) in THF (100 mL) at 0° C. The reaction mixture was then allowedto warm to rt and stirred for 12 h. On completion, the reaction mixturewas concentrated in vacuo. The crude product was purified by silica gelchromatography (DCM:MeOH=50:1 to 10:1) to give the title compound (2.00g, 58% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=7.99 (s,1H), 7.72 (s, 1H), 6.61 (s, 1H), 6.59 (s, 2H); LC-MS (ESI⁺) m/z 205.9(M+H)⁺.

Step 6—5,7-Dichloropyrido[4,3-d]pyrimidin-4(3H)-one

A mixture of 4-amino-2,6-dichloro-pyridine-3-carboxamide (3.00 g, 14.6mmol) and triethyl orthoformate (53.4 g, 360 mmol, 60 mL) was heated to150° C. for 3 hrs. On completion, the reaction mixture was concentratedin vacuo and the residue was triturated with PE/EA=1:1 (5 mL) to givethe title compound (2.0 g, 64% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.33 (s, 1H), 7.72 (s, 1H).

2-[2-[2-[2-[2-(Benzyloxvcarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylMethane Sulfonate (Intermediate FC)

To a solution of benzylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (500mg, 1.35 mmol, Intermediate AJ) in dichloromethane (6 mL) was addedtriethylamine (273 mg, 2.70 mmol, 374 uL) and MsCl (185 mg, 1.62 mmol,125 uL) at 0° C. The reaction mixture was stirred at rt for 1 hour. Oncompletion, the reaction mixture was diluted with water (100 mL), andextracted with ethyl acetate (3×100 mL). Then the combined organic layerwas dried over Na₂SO₄ and concentrated in vacuo to give the titlecompound (600 mg, 98% yield) as a yellowish oil.

3-Oxo-1-phenyl-2,7,10-trioxa-4-azadodecan-12-yl Methanesulfonate(Intermediate FD)

Step 1—Benzyl N-[2-[2-(2-hydroxvethoxy)ethoxy]ethyl]carbamate

To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (3.50 g, 23.5 mmol,CAS #6338-55-2) in CH₃CN (30 mL) and H₂O (30 mL) was added CbzCl (4.80g, 28.1 mmol) and NaHCO₃ (5.91 g, 70.4 mmol). The reaction mixture wasstirred at rt for 12 hours. On completion, the reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (3×20 mL).The combined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by column chromatography (petroleum ether:ethyl acetate=5:1 to1:1) to give the title compound (5.00 g, 75% yield) as a colorless oil.¹H NMR (400 MHz, CDCl₃) δ 7.38-7.29 (m, 5H), 5.47 (s, 1H), 5.11 (s, 2H),3.71 (s, 2H), 3.65-3.56 (m, 8H), 3.43-3.37 (m, 2H).

Step 2—3-Oxo-1-phenyl-2,7,10-trioxa-4-azadodecan-12-vl Methanesulfonate

To a solution of benzyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate(2.00 g, 7.06 mmol) in DCM (30 mL) was added TEA (2.14 g, 21.2 mmol,2.94 mL) and MsCl (1.05 g, 9.18 mmol, 710 uL) at 0° C. The reactionmixture was then allowed to warm to rt and stirred for 0.5 hr. Oncompletion, the reaction mixture was quenched with saturated citric acid(5 mL), and extracted with dichloromethane (3×50 mL). The combinedorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title compound(2.4 g, 94% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ7.39-7.31 (m, 5H), 5.24 (s, 1H), 5.11 (s, 2H), 4.38-4.34 (m, 1H),4.38-4.34 (m, 1H), 3.76 (dd, J=3.6, 5.2 Hz, 2H), 3.67-3.64 (m, 2H),3.64-3.60 (m, 2H), 3.59-3.54 (m, 2H), 3.40 (q, J=5.2 Hz, 2H), 3.02 (s,3H).

N-[2-[(2,5-dichloropyrimidin-4-yl)amino]-5-methoxy-phenyl]methanesulfonamide(Intermediate FE)

Step 1—1-Benzyloxy-2-methoxy-4-methyl-benzene

To a mixture of 2-methoxy-4-methyl-phenol (25.0 g, 180 mmol) in acetone(460 mL) was added K₂CO₃ (62.5 g, 452 mmol) and BnBr (46.4 g, 271 mmol)under nitrogen atmosphere. The reaction mixture was stirred at 50° C.for 12 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo to remove the acetone. The residue was dilutedwith water (100 mL) and extracted with EA (2×200 mL). The combinedorganic layers was dried over Na₂SO₄, filtered and concentrated in vacuoto give a residue. The residue was purified by column chromatography togive the title compound (40.0 g, 96% yield) as white solid. ¹H NMR (400MHz, CDCl₃) δ 7.49-7.43 (m, 2H), 7.42-7.27 (m, 3H), 6.83-6.73 (m, 2H),6.69-6.63 (m, 1H), 5.15 (s, 2H), 3.90 (s, 3H), 2.32 (s, 3H).

Step 2—1-Benzyloxy-2-methoxy-4-methyl-5-nitro-benzene

A stirred mixture of 1-benzyloxy-2-methoxy-4-methyl-benzene (17.5 g,76.6 mmol) in HOAc (60 mL) was cooled to 4-6° C. and a mixture ofconcentrated HNO₃ (49.0 g, 778 mmol) in HOAc (17 mL) was added dropwise.The reaction mixture was stirred at 4-6° C. for 3 hours. On completion,the reaction mixture was poured into 100 mL of an ice-H₂O mixture. Themixture was filtered and the solid precipitate was washed with water.The solid was dried in vacuo to give the title compound (20.0 g, 95%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.73 (s, 1H),7.49-7.33 (m, 5H), 7.09 (s, 1H), 5.17 (s, 2H), 3.90 (s, 3H), 2.54 (s,3H).

Step 3—5-Benzyloxy-4-methoxy-2-methyl-aniline

To a mixture of 1-benzyloxy-2-methoxy-4-methyl-5-nitro-benzene (10.0 g,36.5 mmol) in MeOH (100 mL) and H₂O (60 mL) was added Fe (26.5 g, 475mmol) and NH₄Cl (25.4 g, 475 mmol). The reaction mixture was stirred at65° C. for 12 hours. On completion, the reaction mixture was filteredand concentrated in vacuo to remove the MeOH. The residue was dilutedwith water (50 mL), and neutralized with sat. NaHCO₃ (20 mL) until thepH=8-9. The residue was diluted with water (30 mL) and extracted with EA(2×100 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo to give a residue. The residue was purified bycolumn chromatography to give the title compound (1.60 g, 17% yield) asa white solid. LC-MS (ESI⁺) m/z 244.1 (M+H)⁺.

Step 4—N1-(2,5-dichloropyrimidin-4-yl)-4-methoxy-benzene-1,2-diamine

A mixture of 4-methoxybenzene-1,2-diamine (25.0 g, 180 mmol) and DIPEA(28.0 g, 217 mmol) in IPA (150 mL) was stirred at 0° C.2,4,5-trichloropyrimidine (33.1 g, 180 mmol) was then added dropwise andthe mixture was allowed to warm to rt and stirred for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to remove theIPA. The residue was diluted with water (50 mL) and extracted with EA(2×100 mL). The combined organic layer was dried over Na₂SO₄, filteredand concentrated in vacuo to give the title compound (44.0 g, 85% yield)as a pale solid. LC-MS (ESI⁺) m/z 284.9 (M+H)⁺.

Step5—N-[2-[(2,5-dichloropyrimidin-4-yl)amino]-5-methoxy-phenyl]methanesulfonamide

To a mixture ofN1-(2,5-dichloropyrimidin-4-yl)-4-methoxy-benzene-1,2-diamine (8.00 g,28.0 mmol) in pyridine (20 mL) was added MsCl (3.54 g, 30.8 mmol) at 0°C. Then the reaction mixture was then allowed to warm to rt and stirredfor 4 hours. On completion, the reaction mixture was concentrated invacuo. The residue was purified by column chromatography to give thetitle compound (7.00 g, 68% yield) as a pale solid. LC-MS (ESI⁺) m/z362.9 (M+H)⁺.

2-Methoxy-4-methyl-5-nitro-phenol (Intermediate FF)

To a mixture of 1-benzyloxy-2-methoxy-4-methyl-5-nitro-benzene (5.00 g,18.3 mmol, synthesized via Steps 1-2 of Intermediate FE) in DCM (60 mL)was added BCl DCM (1.0 M, 91 mL). Then the reaction mixture was stirredat rt for 8 hours. On completion, the reaction mixture was concentratedin vacuo. The reaction mixture was washed with sat.NaHCO₃ (150 mL) andextracted with DCM (3×100 mL). The organic layer was dried with Na₂SO₄,filtrated and concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (2.80 g, 83% yield) asyellowish solid. LC-MS (ESI⁺) m/z 184.1 (M+H)⁺.

2,3-Dimethoxy-5-nitrophenol (Intermediate FG)

Step 1—2,3-Dimethoxyphenyl Benzenesulfonate

To a solution of 2,3-dimethoxyphenol (10.0 g, 64.8 mmol, 8.47 mL) indichloromethane (200 mL) was added triethylamine (13.1 g, 129 mmol, 17.9mL) at 0° C. Then benzenesulfonyl chloride (13.7 g, 77.8 mmol, 9.96 mL)was added dropwise over 1 hour at 0° C. The mixture was then allowed towarm to rt and stirred for 15 hours. On completion, the reaction mixturewas diluted with water (700 mL), and then extracted with dichloromethane(4×250 mL). The combined organic layers were washed with brine (2×250mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo to give a residue. The residue was purified by silica gelchromatography (petroleum ether:ethyl acetate=10:1) to give the titlecompound (17.0 g, 89% yield) as a light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.85 (t, J=7.2 Hz, 2H), 7.57 (d, J=7.6 Hz, 1H), 7.45 (t, J=8.0Hz, 2H), 6.89-6.87 (m, 1H), 6.78-6.75 (m, 2H), 3.75 (s, 3H), 3.61 (s,3H).

Step 2—2,3-Dimethoxy-5-nitrophenyl Benzenesulfonate

To a solution of (2,3-dimethoxyphenyl) benzenesulfonate (17.0 g, 57.7mmol) in acetic acid (340 mL) was added nitrosoaphyllinic acid (17.0 g,57.7 mmol, 61.2 mL) dropwise over 1 hour at 0° C. The mixture was thenallowed to warm to rt and was stirred for 15 hours. On completion, thereaction mixture was diluted with water 50 mL and extracted with ethylacetate (3×300 mL). The combined organic layers were washed with brine(2×300 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give a residue. The residue purified by columnchromatography (petroleum ether:ethyl acetate=50:1 to 20:1) to give thetitle compound (17.0 g, 86% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.96 (t, J=5.2 Hz, 1H), 7.74 (d, J=4.8 Hz, 1H), 7.63-7.61 (m,5H), 3.96 (s, 3H), 3.88 (s, 3H).

Step 3—2,3-Dimethoxy-5-nitrophenol

To a solution of (2,3-dimethoxy-5-nitro-phenyl) benzenesulfonate (2.80g, 8.25 mmol) in methanol (28.2 mL) was added 20% potassium hydroxidesolution (16.89 mL). The mixture was stirred at 50° C. for 4 hours. Oncompletion, the reaction mixture was concentrated in vacuo to removemethanol. The residue was diluted with water (50 mL), and acidified withHCl until the pH=5-6. The mixture was then filtered, and the solidprecipitate was collected and dried in vacuo to give the title compound(1.40 g, 85% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.45 (d,J=2.8 Hz, 1H), 7.34 (d, J=2.8 Hz, 1H), 5.94 (s, 1H), 3.95 (s, 3H), 3.83(s, 3H).

(±)-Tert-Butyl2-ethyl-4-[5-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate(Intermediate FH)

Step 1—(±)-Tert-Butyl4-(5-acetyl-2-pyridyl)-2-ethyl-piperazine-1-carboxylate

To a solution of 1-(6-chloro-3-pyridyl)ethanone (4.00 g, 24.9 mmol; CAS#36357-38-7) in ACN (8 mL) was added DIPEA (9.67 g, 74.8 mmol) and(±)-tert-butyl 2-ethylpiperazine-1-carboxylate (6.41 g, 29.9 mmol; CAS#393781-71-0). The reaction mixture was stirred at 85° C. for 12 hours.On completion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by column chromatography (petroleumether:ethyl acetate=30:1 to 5:1) to give the title compound (8.30 g,100% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.75 (d, J=2.0Hz, 1H), 8.03 (dd, J=2.4, 9.2 Hz, 1H), 6.58 (d, J=8.8 Hz, 1H), 4.34 (d,J=13.2 Hz, 1H), 4.27 (d, J=10.4 Hz, 1H), 4.13 (q, J=7.2 Hz, 1H), 4.02(s, 1H), 3.27 (dd, J=4.0, 13.2 Hz, 1H), 3.20-3.04 (m, 2H), 2.51 (s, 3H),1.63-1.50 (m, 2H), 1.49 (s, 9H), 0.90 (t, J=7.2 Hz, 3H).

Step 2—(±)-Ethyl1-(4-bromo-3,5-dimethyl-phenyl)-5-phenyl-pyrazole-4-carboxylate

A mixture of (±)-tert-butyl4-(5-acetyl-2-pyridyl)-2-ethyl-piperazine-1-carboxylate (8.30 g, 24.9mmol) and 1,1-dimethoxy-N,N-dimethyl-methanamine (29.7 g, 249 mmol) washeated to 110° C. for 14 hours. LCMS showed that the starting materialremained, thus the reaction was then heated to 120° C. for another 22hours. On completion, the reaction mixture was concentrated in vacuo togive the residue. The residue was purified by column chromatography(petroleum ether:ethyl acetate=5:1 to ethyl acetate) to give the titlecompound (7.70 g, 80% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ8.73 (d, J=2.4 Hz, 1H), 8.07 (dd, J=2.4, 8.8 Hz, 1H), 7.79 (d, J=12.4Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 5.66 (d, J=12.4 Hz, 1H), 4.31-4.21 (m,2H), 4.12 (q, J=7.2 Hz, 1H), 3.99 (d, J=10.4 Hz, 1H), 3.49 (s, 1H),3.24-2.97 (m, 8H), 1.67-1.52 (m, 2H), 1.49 (s, 9H), 0.90 (t, J=7.2 Hz,3H).

Step 3—(±)-Tert-Butyl2-ethyl-4-[5-(2-sulfanylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate

To a solution of (±)-tert-butyl4-[5-[(Z)-3-(dimethylamino)prop-2-enoyl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate(7.70 g, 19.8 mmol) in ethanol (80 mL) was added thiourea (3.02 g, 39.6mmol) and NaOMe (2.68 g, 49.6 mmol). The reaction mixture was stirred at78° C. for 12 hours. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (7.90 g, 99% yield) asa white solid. LC-MS (ESI⁺) m/z 401.9 (M+H)⁺.

Step 4—(±)-Tert-butyl2-ethyl-4-[5-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate

To a solution of (±)-tert-butyl2-ethyl-4-[5-(2-sulfanylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate(7.90 g, 19.7 mmol) and iodomethane (11.2 g, 78.7 mmol) in THF (80 mL)was added NaOH (1 M, 29.5 mL). The reaction mixture was stirred at rtfor 5 hours. On completion, the reaction mixture was diluted with water(20 mL) and extracted with ethyl acetate (3×20 mL). The combined organiclayers were washed with brine (10 mL), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by column chromatography (petroleum ether:ethyl acetate=5:1 todichloromethane:methanol=100:1) to give the title compound (7.70 g, 94%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J=2.0 Hz,1H), 8.45 (d, J=5.2 Hz, 1H), 8.22 (dd, J=2.4, 8.8 Hz, 1H), 7.24 (d,J=5.2 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 4.31 (d, J=13.2 Hz, 1H), 4.25 (d,J=11.6 Hz, 1H), 4.18-4.08 (m, 1H), 4.03 (s, 1H), 3.25 (dd, J=4.0, 13.2Hz, 1H), 3.21-3.02 (m, 2H), 2.63 (s, 3H), 1.70-1.64 (m, 1H), 1.55 (dd,J=7.2, 14.4 Hz, 1H), 1.50 (s, 9H), 0.91 (t, J=7.2 Hz, 3H).

Step 5—(±)-Tert-Butyl2-ethyl-4-[5-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate

To a solution of (±)-tert-butyl2-ethyl-4-[5-(2-methylsulfanylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate(3.85 g, 9.26 mmol) in acetone (15.0 mL) was added H₂O₂ (5.90 g, 52.0mmol) and disodium dioxide (dioxo) tungsten-dihydrate (306 mg, 926umol). The reaction mixture was stirred at 40° C. for 12 hours. Oncompletion, the reaction mixture was quenched with saturated Na₂SO₄ (20mL) and extracted with dichloromethane (3×100 mL). The combined organiclayer was washed with brine (50 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (dichloromethane:methanol=100:1) to give thetitle compound (4.00 g, 97% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.93 (d, J=2.0 Hz, 1H), 8.78 (d, J=5.6 Hz, 1H), 8.31 (dd,J=2.4, 9.2 Hz, 1H), 7.74 (d, J=5.6 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 4.37(d, J=13.4 Hz, 1H), 4.29 (d, J=8.8 Hz, 1H), 4.19-3.99 (m, 2H), 3.41 (s,3H), 3.30 (dd, J=3.6, 13.2 Hz, 1H), 3.21-3.08 (m, 2H), 1.69-1.61 (m,1H), 1.53 (d, J=7.2 Hz, 1H), 1.50 (s, 9H), 0.92 (t, J=7.2 Hz, 3H).

4-[3-[(Tert-butoxycarbonylamino)methyl]-4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoic Acid(Intermediate FI)

Step 1 —[4-Amino-1-(4-bromophenvl)pyrazol-3-yl]methanol

To a solution of ethyl 1-(4-bromophenyl)-4-nitro-pyrazole-3-carboxylate(3.70 g, 10.8 mmol, synthesized via Steps 1-2 of Intermediate CL) in THF(30.0 mL) was added LiBH₄ (1.18 g, 54.3 mmol). The reaction mixture wasstirred at 50° C. for 3 hrs under N₂. On completion, the reactionmixture was quenched with water (100 mL), concentrated in vacuo toremoved the THF, and filtered. The filtered cake was collected and driedunder vaccuum to give the title compound (1.80 g, 61% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (s, 1H), 7.69-7.62 (m, 4H),5.07-5.03 (m, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.16 (s, 2H).

Step 2—Methyl 4-[4-amino-3-(hydroxymethyl)pyrazol-1-yl]benzoate

To a solution of [4-amino-1-(4-bromophenyl)pyrazol-3-yl]methanol (1.60g, 5.97 mmol) in a mixed solvent of DMF (30.0 mL) and MeOH (30.0 mL) wasadded Pd(dppf)Cl₂·CH₂Cl₂ (487 mg, 596 umol) and TEA (1.81 g, 17.9 mmol,2.49 mL) under N₂. The suspension was degassed in vacuo and purged withCO several times. The mixture was stirred under CO (50 psi) at 80° C.for 36 hours. On completion, the reaction mixture was concentrated invacuo to give the residue. The residue was purified by prep-HPLC (0.1%,HCl) to give the title compound (800 mg, 54% yield) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 8.03-7.93(m, 2H), 4.63 (s, 2H), 3.87 (s, 3H).

Step 3—Methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(hydroxymethyl)pyrazol-1-yl]benzoate

To a solution of methyl4-[4-amino-3-(hydroxymethyl)pyrazol-1-yl]benzoate (400 mg, 1.62 mmol)and2-[2-[tertbutoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (626 mg, 1.62 mmol, Intermediate CM) in DMF (3.00 mL) was addedDIPEA (418 mg, 3.24 mmol). The reaction mixture was stirred at 25° C.for 0.5 hr. Then, HATU (676 mg, 1.78 mmol) was added. The resultingreaction mixture was stirred at 25° C. for 0.5 hr. On completion, thereaction mixture was quenched with water (15 mL), and a white solidprecipitation formed, which was filtered. The filter cake was dried invacuo to give the title compound (920 mg, 92% yield) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.90 (s, 1H), 8.66 (d, J=5.2 Hz,1H), 8.10-8.04 (m, 2H), 8.02-7.96 (m, 2H), 7.73-7.70 (m, 2H), 7.83-7.75(m, 1H), 4.91-4.87 (m, 2H), 4.80 (d, J=5.2 Hz, 2H), 3.87 (s, 3H), 1.53(s, 9H).

Step 4—Methyl4-[3-(azidomethyl)-4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(hydroxymethyl)pyrazol-1-yl]benzoate (500mg, 810 umol) in THF (15.0 mL) was added DPPA (334 mg, 1.22 mmol) andDBU (308 mg, 2.03 mmol) at 0° C. The mixture was stirred at 25° C. for 3hr. On completion, the mixture was diluted with H₂O (50 mL), thenextracted with DCM (3×30 mL). The organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (520 mg, 70% yield) as yellow solid. LC-MS (ESI⁺) m/z 642.3(M+H)⁺.

Step 5—Methyl4-[3-[(tert-butoxycarbonylamino)methyl]-4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

To a solution of methyl4-[3-(azidomethyl)-4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate(520 mg, 810 umol) and (Boc)₂O (265 mg, 1.22 mmol) in MeOH (10.0 mL) wasadded Pd/C (100 mg, 810 umol). The mixture was stirred at 25° C. for 3hrs under H₂ (15 psi). On completion, the mixture was filtered andconcentrated in vacuo. The mixture was purified by reverse phase (0.10%FA) to give the title compound (500 mg, 86% yield) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H), 9.05 (s, 1H), 8.95 (s, 1H), 8.64(d, J=5.2 Hz, 1H), 8.35 (s, 1H), 8.09 (s, 1H), 8.07 (s, 1H), 8.00 (s,1H), 7.98 (s, 1H), 7.86 (d, J=5.2 Hz, 1H), 7.79 (s, 1H), 4.91 (d, J=8.8Hz, 2H), 4.29 (d, J=6.8 Hz, 2H), 3.88 (s, 3H), 1.52 (s, 9H), 1.36 (s,9H).

Step6—4-[3-[(Tert-butoxycarbonylamino)methyl]-4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoic Acid(8)—Notebook Page: EW7002-283

To a solution of methyl4-[3-[(tert-butoxycarbonylamino)methyl]-4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate(160 mg, 223 umol) in a mixed solvent of THF (20.0 mL), H₂O (5.00 mL)and MeOH (5.00 mL) was added LiOH (26.7 mg, 1.12 mmol). The mixture wasstirred at 25° C. for 16 hrs. On completion, the mixture was acidifiedwith 1N HCl solution until the pH=5. The mixture was diluted with H₂O(50 mL), and extracted with EA (3×30 mL). The organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (70.0 mg, 44% yield) as white solid. LC-MS (ESI⁺) m/z702.4 (M+H)⁺.

2-[2-[2-[2-(4-Iodophenoxy)ethoxy]ethoxy]ethoxy]ethanamine (IntermediateFJ)

Step 1—Tert-ButylN-[2-[2-[2-[2-(4-iodophenoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of 4-iodophenol (1 g, 4.55 mmol) and2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy] ethoxy]ethoxy]ethylmethanesulfonate (1.69 g, 4.55 mmol, Intermediate AO) in DMF (15 mL) wasadded K₂CO₃ (1.57 g, 11.3 mmol), and the reaction mixture was stirred at100° C. for 12 hr. On completion, the mixture was diluted with H2O (30mL), then extracted with EA (2×40 mL), and the organic phase wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (1.00 g,44% yield) as yellow oil. LC-MS (ESI⁺) m/z 496.2 (M+H)⁺.

Step 2—2-[2-[2-[2-(4-Iodophenoxy)ethoxy]ethoxy]ethoxy]ethanamine

To a solution of tert-butylN-[2-[2-[2-[2-(4-iodophenoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate (0.9g, 1.82 mmol) in DCM (2 mL) was added HCl/dixoane (4 M, 2.00 mL), andthe reaction mixture was stirred at 20° C. for 20 mins. On completion,the residue was concentrated in vacuo to give the title compound (800mg, 99% yield) as yellow oil. LC-MS (ESI⁺) m/z 396.1 (M+1)⁺.

2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]acetaldehyde(Intermediate FK)

Step1—2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-(2-hydroxyethoxy)ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of 2-[2-(2-aminoethoxy)ethoxy]ethanol (1.80 g, 12.0 mmol,CAS #6338-55-2) and2-(2,6-dioxo-3-piperidyl)-4-fluoroisoindoline-1,3-dione (4.00 g, 14.4mmol, Intermediate R) in dioxane (35.0 mL) was added DIPEA (9.36 g, 72.3mmol). The reaction mixture was stirred at 115° C. for 20 hrs. Oncompletion, the mixture was concentrated in vacuo to remove the solvent.The residue was purified by silica gel chromatography (PE:EA=1:1) togive the title compound (2.90 g, 59% yield) as yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.28 (s, 1H), 7.50 (dd, J=7.2, 8.4 Hz, 1H), 7.11 (d, J=7.2Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.57 (t, J=5.2 Hz, 1H), 4.96-4.85 (m,1H), 3.77-3.67 (m, 8H), 3.64-3.59 (m, 2H), 3.48 (q, J=5.2 Hz, 2H),2.92-2.70 (m, 3H), 2.62 (s, 1H), 2.17-2.08 (m, 1H).

Step2—2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]acetaldehyde(11)—Notebook Page: EW7002-288

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-(2-hydroxyethoxy)ethoxy]ethylamino]isoindoline-1,3-dione(200 mg, 493 umol) in DCM (10.0 mL) was added DMP (209 mg, 493 umol).The mixture was stirred at 25° C. for 16 hrs. On completion, the mixturewas diluted with DCM (30 mL), and extracted with saturated Na₂S2O₃ (2×30mL) and saturated NaHCO₃ (2×30 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (140 mg, 70% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ9.74 (s, 1H), 8.15 (s, 1H), 7.52 (t, J=7.6 Hz, 1H), 7.14 (d, J=7.2 Hz,1H), 6.97-6.90 (m, 1H), 6.57-6.49 (m, 1H), 4.97-4.89 (m, 1H), 3.83-3.65(m, 10H), 2.17-2.11 (m, 1H), 1.91-1.87 (m, 1H), 1.87-1.83 (m, 1H),1.31-1.03 (m, 1H).

Tert-Butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(Intermediate FL)

To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (1.20 g,4.02 mmol, CAS #201940-08-1),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.12 g, 4.43 mmol) in DMSO (20.0 mL) was added KOAc (1.18 g, 12.0 mmol)and Pd(PPh₃)₄ (139 mg, 120 umol). The mixture was stirred at 80° C. for16 hours under N₂. On completion, the mixture was diluted with H₂O (50mL), and extracted with EA (3×30 mL). The organic layers were washedwith brine (3×30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The mixture was purified by prep-HPLC (reservephase (0.1% FA)) to give the title compound (500 mg, 36% yield) asyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.32-7.29 (m, 1H),7.25 (d, J=7.6 Hz, 1H), 4.74-4.66 (m, 4H), 1.54 (s, 9H), 1.37 (s, 12H).

Tert-Butyl5-[4-amino-3-(trifluoromethyl)pyrazol-1-yl]isoindoline-2-carboxylate(Intermediate FM)

Step 1 —(2-Tert-butoxycarbonylisoindolin-5-yl)boronic Acid

To a solution of tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate(500 mg, 1.45 mmol, Intermediate FL) in a mixed solvent of THF (20.0 mL)and H₂O (4.00 mL) was added NaIO₄ (929 mg, 4.34 mmol). The mixture wasstirred at 25° C. for 0.5 hr. HCl (3 M, 965 uL) was added to themixture; and the mixture was stirred at 25° C. for 1.5 hrs. Oncompletion, the mixture was diluted with H₂O (30 mL), and extracted withEA (3×30 mL). The organic layers were washed with brine (3×20 mL), theorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The mixture was purified by prep-HPLC (reversephase (0.10% FA)) to give the title compound (260 mg, 68% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (s, 2H), 7.72 (s, 1H),7.70 (s, 1H), 7.29 (t, J=6.4 Hz, 1H), 4.64-4.53 (m, 4H), 1.46 (s, 9H).

Step 2—Tert-Butyl5-[4-nitro-3-(trifluoromethyl)pyrazol-1-yl]isoindoline-2-carboxylate

To a solution of 4-nitro-3-(trifluoromethyl)-1H-pyrazole (378 mg, 2.09mmol, synthesized via Step 1 of Intermediate DE), (2-tert-butoxycarbonylisoindolin-5-yl)boronic acid (660 mg, 2.51 mmol) in DCM (20.0 mL) wasadded Cu(OAc)₂ (569 mg, 3.14 mmol) and pyridine (661 mg, 8.36 mmol). Themixture was stirred at 25° C. for 12 hrs under O₂ (15 psi). Oncompletion, the mixture was concentrated in vacuo then washed with NH₃H2O (5 mL), filtered and the solid was dried in vacuo. The mixture wastriturated again with MeOH (5 mL), then filtered and the solid was driedin vacuo to give the title compound (400 mg, 48% yield) as white solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (d, J=6.8 Hz, 1H), 7.93 (d, J=12.8 Hz,1H), 7.90-7.85 (m, 1H), 7.59-7.52 (m, 1H), 4.71-4.60 (m, 4H), 1.47 (s,9H).

Step 3—Tert-Butyl5-[4-amino-3-(trifluoromethyl)pyrazol-1-yl]isoindoline-2-carboxylate(7)—Notebook Page: EW7002-281

To a solution of tert-butyl5-[4-nitro-3-(trifluoromethyl)pyrazol-1-yl]isoindoline-2-carboxylate(260 mg, 652 umol) in a mixed solvent of DCM (10.0 mL) and MeOH (10.0mL) was added Pd/C (50.0 mg). Then the reaction mixture was stirred at25° C. for 16 hrs under H₂ (15 psi). On completion, the mixture wasfiltered and concentrated in vacuo to give the title compound (240 mg,80% yield) as white solid. LC-MS (ESI⁺) m/z 369.2 (M+H)⁺.

4-(4-Aminobutylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate FN)

Step 1—Tert-ButylN-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (1.50 g, 5.43mmol, Intermediate R) and tert-butyl N-(4-aminobutyl)carbamate (1.02 g,5.43 mmol, CAS #33545-98-1) in dioxane (15 mL) was added DIPEA (2.81 g,23 mmol). The reaction mixture was stirred at 115° C. for 24 hours. Oncompletion, the mixture was concentrated in vacuo to remove the solvent.The residue was purified by silica gel chromatography to give the titlecompound (0.96 g, 40% yield) as a yellow solid. LC-MS (ESI⁺) m/z 445.2(M+H)⁺.

Step2—4-(4-Aminobutylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butyl]carbamate (0.96 g, 2.16 mmol) in DCM (5 mL) was added HCl/dioxane (4 M,10 mL). The reaction mixture was stirred at 25° C. for 3 hours. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (0.82 g, 100% yield, HCl) as a yellow solid. The crude productwas used for the next step directly without further purification. LC-MS(ESI⁺) m/z 345.1 (M+H)⁺.

Tert-Butyl N-(3-oxopropyl)carbamate (Intermediate FO)

To a solution of DMSO (2.23 g, 28.53 mmol, 2.23 mL, 2.5 eq) in DCM (15mL) was added a solution of (COCl)₂ (2.90 g, 22.8 mmol) in DCM (10 mL)dropwise at −70° C. The mixture was stirred at −70° C. for 10 minutes.Then a solution of tert-butyl N-(3-hydroxypropyl)carbamate (2.00 g, 11.4mmol, CAS #58885-58-8) in DCM (15 mL) was added into the above mixtureslowly. After stirred at −70° C. for 50 minutes, TEA (6.93 g, 68.5 mmol)was added and the reaction mixture was stirred at −70° C. for 0.5 hour.On completion, the mixture was quenched with water (30 mL) andseparated. The aqueous phase was extracted with DCM (2×30 mL). Then theorganic phase was combined and washed with brine (100 mL), dried overNa₂SO₄ and concentrated in vacuo to give the title compound (1.70 g, 86%yield) as yellow oil. The residue was used for the next step directlywithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 9.80 (s, 1H),5.01-4.87 (m, 1H), 3.41 (q, J=6.0 Hz, 2H), 2.70 (t, J=6.0 Hz, 2H), 1.42(s, 9H).

4-[4-(3-Aminopropylamino)butylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate FP)

Step 1—Tert-ButylN-[3-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butylamino]propyl]carbamate

To a solution of tert-butyl N-(3-oxopropyl)carbamate (0.10 g, 577 umol,Intermediate FO) and4-(4-aminobutylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(264 mg, 693 umol, HCl, Intermediate FN) in THF (20 mL) was added KOAc(113 mg, 1.15 mmol). One hour later, NaBH(OAc)₃ (245 mg, 1.15 mmol) wasadded into the above mixture. The reaction mixture was stirred at 25° C.for 72 hours. On completion, the mixture was concentrated in vacuo. Theresidue was purified by reverse phase (0.1% HCl condition) to give thetitle compound (60.0 mg, 21% yield) as a yellow solid. LC-MS (ESI⁺) m/z502.1 (M+H)⁺.

Step2—4-[4-(3-Aminopropylamino)butylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[3-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]butylamino]propyl]carbamate (60.0 mg, 120 umol) in DCM (2 mL) was addedHCl/dioxane (4 mL). The reaction mixture was stirred at 25° C. for 0.5hour. On completion, the mixture was concentrated in vacuo to give thetitle compound (50.0 mg, 95% yield, HCl) as a yellow solid. The residuewas used for the next step directly without further purification. LC-MS(ESI⁺) m/z 402.1 (M+H)⁺.

Tert-Butyl N-[3-[4-(aminomethyl)imidazol-1-yl]propyl]carbamate(Intermediate FO)

Step 1—Methyl 1H-imidazole-4-carboxylate

To a mixture of 1H-imidazole-4-carboxylic acid (5.00 g, 44.6 mmol, CAS#1072-84-0) in MeOH (50 mL) was added SOCl₂ (10.6 g, 89.2 mmol, 6.47mL). The reaction mixture was stirred at 70° C. for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (5.60 g, 99% yield) as white solid. The residue was usedto the next step directly without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 9.29-9.25 (m, 1H), 8.37 (s, 1H), 3.87 (s, 3H).

Step 2—Methyl1-[3-(tert-butoxycarbonylamino)propyl]imidazole-4-carboxylate

To a mixture of methyl 1H-imidazole-4-carboxylate (3.10 g, 24.5 mmol) inACN (50 mL) was added K₂CO₃ (11.2 g, 81.1 mmol) and tert-butylN-(3-bromopropyl)carbamate (11.7 g, 49.1 mmol, CAS #83948-53-2). Thereaction mixture was stirred at 25° C. for 16 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, PE:EA=5:1) to give the title compound (4.00g, 57% yield) as colourless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s,1H), 7.83 (s, 1H), 7.00 (s, 1H), 4.10-4.08 (m, 2H), 3.80 (s, 3H),2.99-2.88 (m, 2H), 1.90-1.88 (m, 2H), 1.45 (s, 9H).

Step 3—Tert-Butyl N-[3-[4-(hydroxymethyl)imidazol-1-yl]propyl]carbamate

To a mixture of methyl1-[3-(tert-butoxycarbonylamino)propyl]imidazole-4-carboxylate (3.00 g,10.5 mmol) in THF (50 mL) was added LiAlH₄ (602 mg, 15.8 mmol) at 0° C.The reaction mixture was stirred at 20° C. for 2 hours. On completion,the reaction mixture was quenched with water (3 mL) and NaOH solution(15%, 5 mL) at 0° C., then Na₂SO₄ (20 g) was added. Then the mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (2.50 g, 92% yield) as colourless oil. The residue was used tothe next step directly without further purification. LC-MS (ESI⁺) m/z256.2 (M+H)⁺.

Step 4—Tert-Butyl N-[3-[4-(azidomethyl)imidazol-1-yl]propyl]carbamate(6)—Notebook Page: EW5435-653

To a mixture of tert-butylN-[3-[4-(hydroxymethyl)imidazol-1-yl]propyl]carbamate (1.00 g, 3.92mmol) and DPPA (1.62 g, 5.88 mmol, 1.27 mL) in THF (20 mL) was added DBU(1.49 g, 9.79 mmol, 1.48 mL) at 0° C. The reaction mixture was stirredat 25° C. for 12 hours. On completion, the reaction mixture wasconcentrated in vacuo. The residue was diluted with water (10 mL) andextracted with EA (3×10 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(1.10 g, 100% yield) as light yellow oil. The residue was used to thenext step directly without further purification. LC-MS (ESI⁺) m/z 281.3(M+H)⁺.

Step 5—Tert-Butyl N-[3-[4-(aminomethyl)imidazol-1-yl]propyl]carbamate

To a mixture of tert-butylN-[3-[4-(azidomethyl)imidazol-1-yl]propyl]carbamate (1.10 g, 3.92 mmol)in MeOH (50 mL) was added Pd/C (500 mg, 10 wt %). The reaction mixturewas stirred at 25° C. for 3 hours under H₂ (15 Psi) atmosphere. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (950 mg, 95% yield) as light yellow oil. Theresidue was used in the next step directly without further purification.LC-MS (ESI⁺) m/z 255.3 (M+H)⁺.

4-[2-[2-[2-(Aminomethyl)-1-piperidyl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidylbisoindoline-1,3-dione (Intermediate FR)

Step 1—Tert-ButylN-[[1-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2-piperidyl]methyl]carbamate

To a solution of2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethanesulfonate (500 mg, 1.14 mmol, synthesized via Steps 1-2 ofExample 184) in CH₃CN (20 mL) was added tert-butyl N-(2-piperidylmethyl)carbamate (488 mg, 2.28 mmol, CAS #141774-61-0), NaHCO₃ (287 mg, 3.41mmol) and KI (18.9 mg, 114 umol). The mixture was stirred at 80° C. for16 hours. On completion, the mixture was concentrated in vacuo. Theresidue was purified by reversed phase flash to give the title compound(450 mg, 71% yield) as yellow solid. LC-MS (ESI⁺) m/z 558.4 (M+H)⁺.

Step2—4-[2-[2-[2-(Aminomethyl)-1-piperidyl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[[1-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2-piperidyl]methyl]carbamate (450 mg, 807 umol) in DCM (5mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 20° C.for 2 hours. On completion, the mixture was concentrated in vacuo togive the title compound (360 mg, 91% yield) as yellow solid. LC-MS(ESI⁺) m/z 458.3 (M+H)⁺.

4-[2-[2-(2-Aminoethoxy)ethylamino]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate FS)

Step 1—Tert-Butyl N-[2-(2-oxoethoxy)ethyl]carbamate

To a solution of DMSO (1.90 g, 24.4 mmol) in DCM (10 mL) was added asolution of (COC)₂ (2.47 g, 19.5 mmol) in DCM (10 mL) dropwise at −70°C. The mixture was stirred at this temperature for 10 minutes. Then asolution of tert-butyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (2 g, 9.74mmol, CAS #139115-91-6) in DCM (15 mL) was added into the above mixtureslowly. After stirring at −70° C. for 50 minutes, TEA (7.89 g, 78.0mmol) was added and the reaction mixture was stirred at −70° C. for 0.5hour. On completion, the mixture was quenched with water (30 mL) andseparated. The aqueous phase was extracted with DCM (2×30 mL). Then theorganic phase was combined and washed with brine (100 mL), dried overNa₂SO₄ and concentrated in vacuo to give the title compound (1.30 g,crude) as yellow oil.

Step 2—Tert-ButylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]ethoxy]ethyl]carbamate

To a solution of4-(2-aminoethylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(202 mg, 572 umol, HCl, Intermediate DJ) and tert-butylN-[2-(2-oxoethoxy)ethyl]carbamate (90.0 mg, 443 umol) in THF (20 mL) wasadded KOAc (102 mg, 1.04 mmol). One hour later, NaBH(OAc)₃ (220 mg, 1.04mmol) was added into the above mixture. The reaction mixture was stirredat 25° C. for 17 hours. On completion, the reaction mixture wasconcentrated in vacuo. The residue was purified by reverse phase (0.1%HCl condition) to give the title compound (80.0 mg, 31% yield) as ayellow solid. LC-MS (ESI⁺) m/z 504.1 (M+H)⁺.

Step3—4-[2-[2-(2-Aminoethoxy)ethylamino]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]ethoxy]ethyl]carbamate (75.0 mg, 149 umol) in DCM (2 mL) wasadded HCl/dioxane (2 mL). The reaction mixture was stirred at 25° C. for0.5 hour. On completion, the mixture was concentrated in vacuo to givethe title compound (65.0 mg, 99% yield, HCl) as a yellow solid. LC-MS(ESI⁺) m/z 404.1 (M+H)⁺.

4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate FT)

Step 1—4-Bromoisobenzofuran-1,3-dione

A solution of 3-bromophthalic acid (5.00 g, 20.4 mmol, CAS #116-69-8) in(Ac)₂O (20.4 mmol, 20 mL) was stirred at 120° C. for 12 hours. Thereaction mixture was then stirred at 25° C. for 16 hours. On completion,the mixture was concentrated in vacuo to give the title compound (4.60g, 99% yield) as yellow solid. LC-MS (ESI⁺) m/z 227.1 (M+H)⁺.

Step 2—4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of 4-bromoisobenzofuran-1,3-dione (4.60 g, 20.2 mmol) and3-aminopiperidine-2,6-dione (3.67 g, 22.2 mmol, HCl, CAS #24666-56-6) inHOAc (40 mL) was added KOAc (6.16 g, 62.8 mmol), the reaction mixturewas stirred at 90° C. for 16 hr. On completion, the mixture was cooledto 25° C. and diluted with ice water (800 mL), and then stirred at 0° C.for 0.5 hr. The reaction mixture was filtered and the filter cake wasdried in vacuo to give the title compound (6.8 g, 99% yield) as graysolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H), 8.19-7.65 (m, 3H),5.41-4.91 (m, 1H), 3.35 (s, 1H), 3.05-2.85 (m, 1H), 2.72-2.54 (m, 2H),2.09 (s, 1H).

4-(3-Aminopropyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate FU)

Step 1—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynyl]carbamate

To a solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1.00 g, 2.97 mmol, Intermediate FT) and tert-butylN-prop-2-ynylcarbamate (598 mg, 3.86 mmol, CAS #92136-39-5) in DMF (6mL) was added TEA (5.40 g, 53.3 mmol, 7.43 mL), CuI (56.4 mg, 296 umol)and Pd(PPh₃)₂Cl₂ (208 mg, 296 umol). The reaction mixture was heated at80° C. for 30 minutes under microwave. On completion, the reactionmixture was concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (1.20 g, 98% yield) as yellowsolid. LC-MS (ESI⁺) m/z 434.0 (M+Na)⁺.

Step 2—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propyl]carbamate

To a mixture of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynyl]carbamate (520 mg, 1.26 mmol) in THF (20 mL) was added Pd(OH)₂/C (150 g,10 wt %) and Pd/C (130 mg, 10 wt %). The reaction mixture was stirred at25° C. for 12 hours under H₂ (15 Psi) atmosphere. On completion, thereaction mixture was filtered and concentrated in vacuo to give thetitle compound (0.52 g, 99% yield) as light yellow solid. LC-MS (ESI⁺)m/z 438.3 (M+Na)⁺.

Step 3—4-(3-Aminopropyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propyl]carbamate(520 mg, 1.25 mmol) in DCM (3 mL) was added HCl/dioxane (4 M, 3 mL). Thereaction mixture was stirred at 25° C. for 2 hours. On completion, thereaction mixture was concentrated in vacuo to give the title compound(520 mg, 99% yield, HCl) as light yellow solid. LC-MS (ESI⁺) m/z 316.1(M+H)⁺.

4-[3-(5-Aminopentylamino)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate FV)

Step 1—Tert-ButylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propylamino]pentyl]carbamate

To a mixture of4-(3-aminopropyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (445mg, 1.27 mmol, HCl, Intermediate FU) in THF (5 mL) was added TEA (85.4mg, 844 umol, 117 uL) and tert-butyl N-(5-oxopentyl)carbamate (170 mg,844 umol, Intermediate EK) and HOAc (76.0 mg, 1.27 mmol, 72.4 uL), thenNaBH(OAc)₃ (358 mg, 1.69 mmol) was added. The reaction mixture wasstirred at 25° C. for 5 hours under N₂ atmosphere. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byprep-HPLC (0.1% FA condition) to give the title compound (200 mg, 47%yield) as light yellow oil. LC-MS (ESI⁺) m/z 501.4 (M+H)⁺.

Step2—4-[3-(5-Aminopentylamino)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propylamino]pentyl]carbamate (170 mg, 339 umol) in DCM (5 mL) was added HCl/dioxane(4 M, 8 mL). The reaction mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (170 mg, 99% yield) as light yellow solid. LC-MS (ESI⁺)m/z 401.2 (M+H).

Methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate (IntermediateFW)

Step 1—Methyl4-[4-(benzhydrylideneamino)-3-(difluoromethyl)pyrazol-1-yl]benzoate

A mixture of methyl 4-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]benzoate(0.15 g, 453 umol, synthesized via Steps 1-2 of Intermediate EB),diphenylmethanimine (205 mg, 1.13 mmol), Pd(OAc)₂ (20.8 mg, 92.4 umol),Xantphos (26.2 mg, 45.3 umol) and Cs₂CO₃ (448 mg, 1.38 mmol) in dioxane(3 mL) was degassed and purged with N₂ 3 times, and then the mixture wasstirred at 120° C. for 3 hrs under N₂ atmosphere. On completion, themixture was concentrated, then H₂O (30 mL) was added and the mixture wasextracted with EtOAc (3×30 mL). The organic phase was dried with Na₂SO₄,filtrated and concentrated in vacuo. The residue was purified by flashsilica gel chromatography to give the title compound (0.24 g, 50% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.02-7.95 (m, 2H),7.80-7.73 (m, 2H), 7.51-7.45 (m, 3H), 7.43-7.31 (m, 5H), 7.22-7.19 (m,2H), 7.12-6.82 (m, 1H), 6.37 (s, 1H), 3.85 (s, 3H); LC-MS (ESI⁺) m/z432.1 (M+H)⁺.

Step 2—Methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate

To a solution of methyl4-[4-(benzhydrylideneamino)-3-(difluoromethyl)pyrazol-1-yl]benzoate (215mg, 498 umol) in THF (2 mL) and MeOH (20 mL) was added HCl/MeOH (4 M,124 uL). The mixture was stirred at 25° C. for 30 min. On completion,the mixture was concentrated to give the title compound (0.20 g, 90%yield) as a yellow solid. LC-MS (ESI⁺) m/z 268.1 (M+H)⁺.

4-[4-[[2-[2-(Cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicAcid (Intermediate FX)

Step 1—Methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate

A mixture of methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate(340 mg, 1.27 mmol, Intermediate FW),2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (412 mg, 1.15 mmol, from Steps 1-4 of Intermediate DF), HATU (484mg, 1.27 mmol), DIPEA (411 mg, 3.18 mmol, 554 uL) in DMF (10 mL) wasdegassed and purged with N₂ 3 times. Then the mixture was stirred at 25°C. for 6 hrs. On completion, the mixture was diluted with 50 mL H₂O andthen filtered. The filter cake was dried in vacuo to give the titlecompound (260 mg, 27% yield) as a yellow solid. LC-MS (ESI⁺) m/z 609.2(M+H)⁺.

Step2—4-[4-[[2-[2-(Cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoic Acid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate (200mg, 329 umol) in THF (5 mL) and H₂O (5 mL) and MeOH (1 mL) was addedLiOH (39.4 mg, 1.64 mmol). The mixture was stirred at 25° C. for 6 hrs.On completion, the mixture was concentrated, the residue was dilutedwith H₂O (50 mL) and added 1M HCl to pH=5-6, extracted with EA (3×30mL). The combined organic layers were washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (0.13 g, 95% yield) as a yellow solid. LC-MS (ESI⁺) m/z 595.4(M+H)⁺.

Tert-Butyl N-methyl-N-[2-(2-prop-2-vnoxyethoxy)ethyl]carbamate(Intermediate FY)

Step 1—Ethyl 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]acetate

To a solution of tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (10 g,57.0 mmol) and Rh(OAc)₂ (630 mg, 2.85 mmol) in DCM (100 mL) was added asolution of ethyl 2-diazoacetate (13.0 g, 114 mmol, CAS #623-73-4) inDCM (200 mL) dropwise, and the mixture was stirred at 25° C. for 16hours. On completion, the reaction mixture was washed with water (50mL×4), dried over Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (14.5 g, 97% yield) as light yellow liquid. ¹H NMR (400MHz, CDCl₃) δ 4.21 (q, J=7.2 Hz, 2H), 4.09-4.04 (m, 2H), 3.71-3.59 (m,2H), 3.46-3.38 (m, 2H), 2.92 (s, 3H), 1.44 (s, 9H), 1.27 (t, J=7.2 Hz,3H).

Step 2—Tert-Butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate

To a solution of ethyl2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]acetate (12.4 g, 47.4mmol) in THF (200 mL) was added LiAlH₄ (2.76 g, 71.1 mmol, 98% purity)at 0° C. under N₂ atmosphere. The reaction mixture was stirred at 20° C.for 1 hour. On completion, the mixture was quenched with water (4 mL)and NaOH aqueous solution (15%, 4 mL) at 0° C., filtered and dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(9.40 g, 90% yield) as colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ3.72-3.67 (m, 2H), 3.66-3.54 (m, 4H), 3.50-3.42 (m, 2H), 2.91 (s, 3H),1.46 (s, 9H).

Step 3—Tert-Butyl N-methyl-N-[2-(2-prop-2-vnoxvethoxy)ethyl]carbamate

To a solution of tert-butylN-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (8.70 g, 39.6 mmol) and3-bromoprop-1-yne (5.19 g, 43.6 mmol) in THF (100 mL) was added TBAI(879 mg, 2.38 mmol), KI (987 mg, 5.95 mmol) and KOH (2.62 g, 39.6 mmol,85%). The mixture was stirred at 20° C. for 16 hours. On completion, thereaction mixture was filtered and concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatography(PE:EA=3:1) to give the title compound (4.20 g, 41% yield) as colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 4.21 (d, J=2.4 Hz, 2H), 3.72-3.67 (m,2H), 3.67-3.62 (m, 2H), 3.61-3.55 (m, 2H), 3.45-3.35 (m, 2H), 2.92 (s,3H), 2.43 (t, J=2.4 Hz, 1H), 1.46 (s, 9H).

2-(2,6-Dioxo-3-piperidyl)-4-[3-[2-[2-(methylamino)ethoxy]ethoxy]yl]propyl]isoindoline-1,3-dione(Intermediate FZ)

Step 1—Tert-ButylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethyl]-N-methyl-carbamate

4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.60 g, 1.78mmol, Intermediate FT), CuI (33.9 mg, 178 umol) and Pd(PPh₃)₂Cl₂ (125mg, 178 umol) was taken up into a microwave tube. Then tert-butylN-methyl-N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (458 mg, 1.78 mmol,Intermediate FY), TEA (3.24 g, 32.0 mmol) and DMF (5 mL) were added intothe above tube. The mixture was degassed with N₂ for 5 minutes. Thesealed tube was heated at 80° C. for 30 minutes under microwave. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (460 mg, 43% yield, 85%purity) as yellow oil. LC-MS (ESI⁺) m/z 536.3 (M+Na)⁺.

Step 2—Tert-ButylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethyl]-N-methyl-carbamate

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethyl]-N-methyl-carbamate(460 mg, 761 umol) in THF (5 mL) was added Pd/C (0.2 g, 10% wt) andPd(OH)₂/C (0.2 g, 10% wt). The reaction mixture was stirred at 25° C.for 18 hrs under H₂ (15 Psi). On completion, the mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(450 mg, 100% yield) as yellow oil. LC-MS (ESI⁺) m/z 540.1 (M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-4-[3-[2-[2-(methylamino)ethoxy]ethoxy]propyl]isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethyl]-N-methyl-carbamate (450 mg, 869 umol) in DCM (3 mL) wasadded HCl/dioxane (4 M, 4 mL). The reaction mixture was stirred at 25°C. for 0.5 hr. On completion, the residue was concentrated in vacuo togive the title compound (330 mg, 84% yield, HCl) as yellow oil. LC-MS(ESI⁺) m/z 418.1 (M+H)⁺.

5-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate GA)

To a solution of 3-aminopiperidine-2,6-dione (7.98 g, 48.4 mmol, HClsalt, CAS #24666-56-6), KOAc (13.4 g, 136 mmol) in HOAc (200 mL) wasadded 5-bromoisobenzofuran-1,3-dione (10.0 g, 44.0 mmol, CAS #282-73-5).The mixture was then heated to 90° C. and stirred for 12 hours. Oncompletion, the mixture was cooled down to 25° C. and diluted with water(800 mL), and then filtered to give a filter cake. The filter cake wasstirred in DCM (20 mL) for 1 hour and filtered to give a filter cake.The filter cake was dried in vacuo to give the title compound (9.00 g,60% yield) as a blue solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H),8.15 (d, J=1.2 Hz, 1H), 8.10 (dd, J=1.6, 8.0 Hz, 1H), 7.87 (d, J=8.0 Hz,1H), 5.17 (dd, J=5.6, 12.8 Hz, 1H), 2.95-2.83 (m, 1H), 2.65-2.52 (m,2H), 2.11-2.00 (m, 1H).

4-Amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxamide (IntermediateGB)

Step 1—Methyl 1-[4-(hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carboxylate

To a mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate (8.00 g, 38.5mmol, HCl salt, Intermediate HL), [4-(hydroxymethyl)phenyl]boronic acid(7.03 g, 46.2 mmol, CAS #59016-93-2) and pyridine (18.2 g, 231 mmol) inDCM (130 mL) was added Cu(OAc)₂ (8.40 g, 46.2 mmol). The mixture wasstirred at 25° C. under O₂ (15 psi) for 16 hours. On completion, themixture was concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography (PE:EA=1:1) to give the titlecompound (4.00 g, 36% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.68 (s, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 5.37 (t,J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.94 (s, 3H); LC-MS (ESI⁺) m/z300.0 (M+Na)⁺.

Step 2—1-[4-(Hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carboxamide

To a solution of methyl1-[4-(hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carboxylate (2.30 g, 7.72mmol) in THF (15 mL) was added NH₃ H₂O (22.7 g, 194 mmol, 30% w/w) in asealed tube. The mixture was stirred at 80° C. for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (2.20 g, 97% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.60 (s, 1H), 8.19 (s, 1H), 7.90 (d, J=8.4 Hz, 3H), 7.50 (d,J=8.4 Hz, 2H), 5.37 (s, 1H), 4.56 (d, J=2.4 Hz, 2H).

Step 3—4-Amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxamide

To a solution of1-[4-(hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carboxamide (1.60 g, 6.10mmol) in MeOH (120 mL) was added Pd/C (0.8 g, 10% w/w) under N₂. Thesuspension was degassed in vacuo and purged with H₂ three times. Themixture was stirred under H₂ (15 psi) at 20° C. for 40 minutes. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (1.40 g, 91% yield) asyellow solid; LC-MS (ESI⁺) m/z 233.1 (M+H)⁺.

Tert-ButylN-[4-[4-[[3-carbamoyl-1-(4-formylphenvl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(Intermediate GC)

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (1.24 g, 3.44 mmol, from Steps 1-4 of Intermediate DF) in DMF (25mL) was added DIPEA (1.67 g, 12.9 mmol), HATU (1.96 g, 5.17 mmol) and4-amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxamide (1.00 g, 4.31mmol, Intermediate GB). The mixture was stirred at 20° C. for 2 hours.On completion, the reaction mixture was diluted with water (80 mL),filtered to give a filter cake which was dried in vacuo to give thetitle compound (1.50 g, 60% yield) as brown solid. LC-MS (ESI⁺) m/z574.1 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate (1.5 g,2.62 mmol) in a THF (300 mL) was added DMP (1.22 g, 2.88 mmol), and themixture was stirred at 20° C. for 16 hours. On completion, the reactionmixture was quenched with saturated Na₂S2O₃ (20 mL) and saturated NaHCO₃(20 mL) at 25° C. This reaction mixture was then stirred for 30 minutes,then extracted with CH₂Cl₂ (80 mL×3). The combined organic layers werefiltered and concentrated in vacuo to give the title compound (1 g, 67%yield) as gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 10.04(s, 1H), 9.09 (s, 2H), 8.60 (d, J=5.2 Hz, 1H), 8.25-8.23 (m, 3H), 8.17(s, 1H), 8.07 (d, J=8.4 Hz, 2H), 7.81 (br s, 1H), 7.67 (d, J=4.8 Hz,1H), 3.86 (br d, J=7.2 Hz, 2H), 1.52 (s, 9H), 1.20-1.16 (m, 1H),0.46-0.35 (m, 2H), 0.25-0.22 (m, 2H); LC-MS (ESI⁺) m/z 572.1 (M+H)⁺.

2-(2,6-Dioxo-3-piperidyl)-5-[3-[2-[2-(methylamino)ethoxy]ethoxy]propyl]isoindoline-1,3-dione(Intermediate GD)

Step 1—Tert-ButylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynoxy]ethoxy]ethyl]-N-methyl-carbamate

To a solution of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(3.73 g, 11.0 mmol, Intermediate GA) and tert-butylN-methyl-N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (3.70 g, 14.3 mmol,Intermediate FY) in DMF (30 mL) was added Pd(PPh₃)₂Cl₂ (776 mg, 1.11mmol), TEA (20.1 g, 199 mmol) and CuI (210 mg, 1.11 mmol). The mixturewas heated at 80° C. for 30 minutes under microwave. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by silica gel chromatography (PE:EA=1:1) to givethe title compound (5.50 g, 96% yield) as brown oil. ¹H NMR (400 MHz,CDCl₃) δ 8.09 (s, 1H), 7.91 (s, 1H), 7.87-7.78 (m, 2H), 4.99 (dd, J=5.6,12.4 Hz, 1H), 4.48 (s, 2H), 3.80-3.73 (m, 2H), 3.71-3.66 (m, 2H),3.65-3.58 (m, 2H), 3.45-3.35 (m, 2H), 2.98-2.94 (m, 1H), 2.93 (s, 3H),2.88-2.70 (m, 2H), 2.21-2.13 (m, 1H), 1.46 (s, 9H).

Step 2—Tert-ButylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propoxy]ethoxy]ethyl]-N-methyl-carbamate(19)—Notebook Page: EW5417-733

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynoxy]ethoxy]ethyl]-N-methyl-carbamate(1.00 g, 1.95 mmol) in THF (20 mL) was added Pd/C (0.30 g, 10% w/w) andPd(OH)₂/C (0.30 g, 10% w/w) under N₂ atmosphere. The suspension wasdegassed under vacuum and purged with H₂ three times. The mixture wasstirred under H₂ (15 Psi) at 20° C. for 1 hour. On completion, thereaction mixture was filtered and the filterate was concentrated invacuo to give the title compound (0.95 g, 95% yield) as brown oil. ¹HNMR (400 MHz, CDCl₃) δ 8.08 (s, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.72 (s,1H), 7.59 (dd, J=1.2, 7.6 Hz, 1H), 5.02 (dd, J=5.2, 13.6 Hz, 1H),3.67-3.55 (m, 6H), 3.48 (t, J=6.0 Hz, 2H), 3.44-3.36 (m, 2H), 2.92 (s,3H), 2.91-2.89 (m, 1H), 2.88-2.85 (m, 2H), 2.84-2.68 (m, 2H), 2.19-2.11(m, 1H), 2.00-1.91 (m, 2H), 1.46 (s, 9H); LC-MS (ESI⁺) m/z 540.3(M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-5-[3-[2-[2-(methylamino)ethoxy]ethoxy]propyl]isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propoxy]ethoxy]ethyl]-N-methyl-carbamate (0.95 g, 1.84 mmol) in DCM (20 mL) wasadded HCl/dioxane (4 M, 12 mL). The mixture was stirred at 20° C. for 1hour. On completion, the mixture was concentrated in vacuo to give thetitle compound (0.83 g, 99% yield, HCl salt) as light yellow solid.LC-MS (ESI⁺) m/z 418.3 (M+H)⁺.

N-[3-carbamoyl-1-(4-formylphenvl)pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide(Intermediate GE)

Step 1—Isopropoxycarbonyl4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

To a mixture of4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicacid (500 mg, 1.20 mmol, Intermediate EE) in THF (20 mL) was added TEA(483 mg, 4.78 mmol, 665 uL) and isopropyl carbonochloridate (366 mg,2.99 mmol, 414 uL). The reaction mixture was stirred at −10° C. for 2hours. On completion, the reaction mixture was filtered. The filtratewas used to the next step directly without further purification to givethe title compound (600 mg, 99% yield) as light yellow oil. LC-MS (ESI⁺)m/z 505.0 (M+H)⁺.

Step2—N-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

To a mixture of isopropoxycarbonyl4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate (600 mg, 1.19 mmol) in H₂O (5 mL) and THF (50 mL)was added LiBH₄ (155 mg, 7.14 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 2 hours. On completion, the reaction mixture wasquenched with water (30 mL) under stirring. Then the mixture wasextracted with EA (3×50 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was triturated with DCM/PE (5 mL/30 mL) and filtered to give thetitle compound (250 mg, 51% yield) as light yellow solid. LC-MS (ESI⁺)m/z 405.2 (M+H)⁺.

Step3—N-[3-carbamoyl-1-(4-formylphenvl)pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

To a mixture ofN-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide(250 mg, 618 umol) in DCM (10 mL) and THF (10 mL) was added DMP (524 mg,1.24 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2hours. On completion, the reaction mixture was diluted with Na₂S2O₃ (10mL), NaHCO₃ (10 mL) and stirred for 30 min. Then the mixture wasextracted with DCM (3×10 mL) and the combined organic layers was driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (230 mg, 92% yield) as light yellow solid. LC-MS (ESI⁺) m/z403.2 (M+H)⁺.

Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(Intermediate GF)

Step 1—Isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicacid (250 mg, 420 umol, Intermediate FX) in THF (10 mL) was added TEA(170 mg, 1.68 mmol) and isopropyl carbonochloridate (128 mg, 1.05 mmol).The mixture was stirred at −10° C. for 1 hour. On completion, themixture was filtered and the filtrate was concentrated in vacuo to givethe title compound (280 mg, 90% yield) as yellow solid. LC-MS (ESI⁺) m/z681.3 (M+H)⁺.

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate (280 mg, 411 umol) in THF(30.0 mL) and H₂O (4.00 mL) was added NaBH₄ (62.2 mg, 1.65 mmol). Themixture was stirred at 0° C. for 1 hour. On completion, the mixture wasdiluted with H₂O (50 mL) and extracted with EtOAc (3×30 mL). The organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The mixture was triturated with DCM:PE=1:5 (30 mL), and filtered.The filter cake was dried in vacuo to give the title compound (200 mg,83% yield) as white solid. LC-MS (ESI⁺) m/z 581.3 (M+H)⁺.

Step 3—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (140 mg,241 umol) in DCM (10.0 mL) was added DMP (204 mg, 482 umol). The mixturewas stirred at 15° C. for 2 hours. On completion, the mixture wasdiluted with DCM (30 mL), and washed with saturated Na₂S2O₃ (2×30 mL)and saturated NaHCO₃ (2×30 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (80.0 mg, 57% yield) as white solid. LC-MS (ESI⁺) m/z 579.1(M+H)⁺.

Tert-Butyl N-(5-prop-2-ynoxypentyl)carbamate (Intermediate GG)

Step 1—Tert-Butyl N-(5-hydroxypentyl)carbamate

To a solution of 5-aminopentan-1-ol (21.3 g, 206 mmol) in MeOH (200 mL)was added I₂ (2.63 g, 10.3 mmol) and tert-butoxycarbonyl tert-butylcarbonate (54.2 g, 248 mmol). The mixture was stirred at 25° C. for 12hours. On completion, the mixture was concentrated to give a residue.The residue was purified by silica gel chromatograph to give the titlecompound (40.0 g, 95% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ4.60 (s, 1H), 3.69-3.59 (m, 2H), 3.12 (d, J=5.6 Hz, 2H), 1.9-1.7 (m,1H), 1.61-1.36 (m, 15H).

Step 2—Tert-Butyl N-(5-prop-2-ynoxypentyl)carbamate

To a solution of tert-butyl N-(5-hydroxypentyl)carbamate (5.00 g, 24.6mmol) and 3-bromoprop-1-yne (3.07 g, 25.8 mmol) in THF (100 mL) wasadded TBAI (545 mg, 1.48 mmol) and KI (612 mg, 3.69 mmol). Then KOH(1.38 g, 24.6 mmol) was added into the above mixture. The reactionmixture was stirred at 25° C. for 12 hours. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatograph(PE:EA=5/1) to give the title compound (3.00 g, 50% yield) as a lightyellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.12 (d, J=2.4 Hz, 2H), 3.50 (t,J=6.4 Hz, 2H), 3.11 (q, J=6.4 Hz, 2H), 2.41 (t, J=2.4 Hz, 1H), 1.65-1.55(m, 2H), 1.53-1.33 (m, 13H).

4-[3-(5-Aminopentoxy)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate GH)

Step 1—Tert-ButylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]pentyl]carbamate

4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (500 mg, 1.48mmol, Intermediate FT), CuI (28.2 mg, 148 umol) and Pd(PPh₃)₂C₂ (104 mg,148 umol) was taking up into a microwave tube. Then DMF (10 mL), TEA(2.70 g, 26.7 mmol) and tert-butyl N-(5-prop-2-ynoxypentyl)carbamate(715 mg, 2.97 mmol, Intermediate GG) were added to the tube. The sealedtube was heated to 80° C. and stirred for 0.5 hours. On completion, thereaction mixture was diluted with water (100 mL) and extracted with EA(5×10 mL). The organic phase was dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatograph (EA/PE-1/1) to give the title compound (1.10 g,74% yield) as a white solid. LC-MS (ESI⁺) m/z 498.1 (M+H)⁺.

Step 2—Tert-ButylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]pentyl]carbamate

To a solution of tert-butylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]pentyl]carbamate(0.50 g, 1.00 mmol) in THF (5 mL) was added Pd/C (50.0 mg, 10 wt %) andPd(OH)₂ (50 mg, 10 wt %). The mixture was purged with H₂ gas severaltimes. The mixture was stirred under H₂ (15 psi) at 25° C. for 12minutes. On completion, the reaction mixture was filtered and thefiltrate was concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatograph to give the title compound (380 mg,75% yield) as a yellow gum; LC-MS (ESI⁺) m/z 502.1 (M+H)⁺.

Step3—4-[3-(5-Aminopentoxy)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]pentyl]carbamate (380 mg, 757 umol) in DCM (4 mL) was added HCl/dioxane(4 M, 4 mL). The mixture was stirred at 20° C. for 0.5 hour. Oncompletion, the reaction mixture was concentrated in vacuo to give theproduct (330 mg, 65% yield) as light yellow solid; LC-MS (ESI⁺) m/z402.3 (M+H)⁺.

Tert-Butyl methyl(5-(prop-2-vn-1-yloxy)pentyl)carbamate (IntermediateGI)

Step 1—N-(5-hydroxypentvl)formamide

A solution of 5-aminopentan-1-ol (CAS #2508-29-4) (7 g, 67.9 mmol) inethyl formate (20.1 g, 271 mmol) was heated to 90° C. for 6 hrs. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (8.9 g, 97% yield) as colorless oil. The residue was usedfor the next step without purification. LC-MS (ESI⁺) m/z 132.1 (M+H)⁺.

Step 2—5-(Methylamino)pentan-1-ol

To a solution of LiAlH₄ (3.09 g, 81.4 mmol) in THF (100 mL) was addedN-(5-hydroxypentyl)formamide (8.9 g, 67.8 mmol) slowly at 0° C. Then,the reaction mixture was heated to 80° C. for 2 hrs. On completion, thereaction mixture was quenched with a solution of 15% NaOH (20 mL).Thereafter, 50 g anhydrous sodium sulfate was added, and the mixture wasfiltered. The filtrate was concentrated in vacuo to give the titlecompound (7.95 g, 100% yield, crude) as colorless oil.

Step 3—Tert-Butyl (5-hydroxypentvl)(methyl)carbamate

To a solution of 5-(methylamino)pentan-1-ol (7.95 g, 67.8 mmol) inmethanol (100 mL) was added tert-butoxycarbonyl tert-butyl carbonate(14.8 g, 67.8 mmol, 15.6 mL). The reaction mixture was stirred at 25° C.for 12 hrs. On completion, the reaction mixture was concentrated invacuo. The residue was purified by silica gel chromatography (PE:EA=2:1)to give the title compound (9.6 g, 65% yield) as a colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 3.66 (t, J=6.4 Hz, 2H), 3.25-3.21 (m, 2H), 2.85 (s,3H), 1.65-1.59 (m, 2H), 1.58-1.51 (m, 2H), 1.47 (s, 9H), 1.42-1.33 (m,2H).

Step 4—Tert-Butyl methyl(5-(prop-2-yn-1-yloxy)pentyl)carbamate

To a solution of tert-butyl N-(5-hydroxypentyl)-N-methyl-carbamate (1.00g, 4.60 mmol) and 3-bromoprop-1-yne (575 mg, 4.83 mmol) in THF (10 mL)was added KOH (334 mg, 5.06 mmol, 85% purity), KI (153 mg, 920 umol) andTBAI (340 mg, 920 umol). The reaction mixture was stirred at 20° C. for12 hrs. On completion, the reaction mixture was extracted with ethylacetate (3×50 mL). The combined organic layers was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel chromatography(PE:EA=50:1) to give the title compound (530 mg, 45% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.15 (d, J=2.4 Hz, 2H), 3.53(t, J=6.4 Hz, 2H), 3.24-3.22 (m, 2H), 2.85 (s, 3H), 2.43 (t, J=2.4 Hz,1H), 1.68-1.63 (m, 2H), 1.57-1.53 (m, 2H), 1.47 (s, 9H), 1.41-1.34 (m,2H).

2-(2,6-Dioxopiperidin-3-yl)-4-(3-((5-(methylamino)pentyl)oxy)propyl)isoindoline-1,3-dione(Intermediate GJ)

Step 1—Tert-Butyl(5-((3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)pentvl)(methyl)carbamate

4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (200 mg, 593umol, Intermediate FT), tert-butylN-methyl-N-(5-prop-2-ynoxypentyl)carbamate (152 mg, 593 umol,Intermediate GI), Pd(PPh₃)₂Cl₂ (41.6 mg, 59.3 umol), CuI (11.3 mg, 59.3umol) and TEA (1.08 g, 10.7 mmol, 1.49 mL) were taken up into amicrowave tube in DMF (3 mL) under N₂. The reaction mixture wasde-gassed with N₂ and then the seal tube was heated to 80° C. for 0.5hour. On completion, the reaction mixture was concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE:EA=2:1) to givethe title compound (260 mg, 66% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 8.47 (s, 1H), 7.76 (d, J=7.2 Hz, 1H), 7.71-7.67 (m, 1H),7.65-7.60 (m, 1H), 4.95-4.91 (m, 1H), 4.38 (s, 2H), 3.60 (t, J=6.8 Hz,2H), 3.14 (t, J=6.8 Hz, 2H), 2.83-2.66 (m, 7H), 1.66-1.56 (m, 2H),1.49-1.43 (m, 2H), 1.38 (s, 9H), 1.36-1.30 (m, 2H); LC-MS (ESI⁺) m/z512.1 (M+H)⁺.

Step 2—Tert-Butyl(5-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)pentyl)(methyl) carbamate

To a solution of tert-butylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]pentyl]-N-methyl-carbamate(260 mg, 391 umol) in THF (20 mL) was added Pd(OH)₂/C (26 mg, 10% wt)and Pd/C (26 mg, 10% wt) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (15 Psi) at 25° C. for 12 hours. On completion, the reaction mixturewas filtered and concentrated in vacuo to give the title compound (260mg, 99% yield) as a white solid. LC-MS (ESI⁺) m/z 538.1 (M+Na)⁺.

Step3—2-(2,6-Dioxopiperidin-3-yl)-4-(3-((5-(methylamino)pentyl)oxy)propyl)isoindoline-1,3-dione

To a solution of tert-butylN-[5-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]pentyl]-N-methyl-carbamate(260 mg, 388 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL) underN₂. The mixture was stirred at 25° C. for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(175 mg, 99% yield) as a white solid which was used for the next stepwithout purification. LC-MS (ESI⁺) m/z 416.1 (M+H)⁺.

Tert-Butyl N-methyl-N-(2-prop-2-ynoxyethyl)carbamate (Intermediate GK)

To a solution oftert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (4 g,22.8 mmol, CAS #57561-39-4) and 3-bromoprop-1-yne (2.72 g, 22.8 mmol,1.97 mL) in THF (40 mL) was added TBAI (505 mg, 1.37 mmol), KI (568 mg,3.42 mmol), and KOH (1.28 g, 22.8 mmol), and the reaction mixture wasstirred at 25° C. for 16 hr. On completion, the mixture was filtered,and the filtrate was concentrated in vacuo to give a residue. Theresidue was purified by flash silica gel chromatography (PE/EA=5/1,Rf=0.6) to give the title compound (2.9 g, 59% yield) as yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 4.15 (d, J=2.4 Hz, 2H), 3.64 (s, 2H), 3.41 (s,2H), 2.92 (s, 3H), 2.53-2.35 (m, 1H), 1.46 (s, 9H)

2-(2,6-Dioxo-3-piperidyl)-4-[3-[2-(methylamino)ethoxy]propyl]isoindoline-1,3-dione(Intermediate GL)

Step 1—Tert-ButylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethyl]-N-methyl-carbamate

To a solution of tert-butyl N-methyl-N-(2-prop-2-ynoxyethyl)carbamate(379 mg, 1.78 mmol, Intermediate GK) and4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (300 mg, 889umol, Intermediate FT) in DMF (4 mL) was added TEA (1.62 g, 16.0 mmol,2.23 mL), CuI (16.9 mg, 88.9 umol) and Pd(PPh₃)₂Cl₂ (62.4 mg, 88.9umol), the reaction mixture was heated at 80° C. for 30 min undermicrowave. On completion, the mixture was concentrated in vacuo to givea residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate-5/1 to 1/0, Rf=0.29) to give the titlecompound (430 mg, 100% yield) as yellow oil. LC-MS (ESI⁺) m/z 370.2(M+H−100)⁺.

Step 2—Tert-ButylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethyl]-N-methyl-carbamate

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethyl]-N-methyl-carbamate (430 mg, 915 umol) in THF (10 mL) was addedPd(OH)₂/C (250 mg, 10 wt %) and Pd/C (250 mg, 10 wt %), and the reactionmixture was stirred at 25° C. under H₂ (15 psi) for 16 hr. Oncompletion, the residue was filtered and the filtrate was concentratedin vacuo to give the title compound (350 mg, 80% yield) as brown solid.LC-MS (ESI⁺) m/z 496.2 (M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-4-[3-[2-(methylamino)ethoxy]propyl]isoindoline-1,3-dione

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethyl]-N-methyl-carbamate(350 mg, 739 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL), andthe reaction mixture was stirred at 25° C. for 20 mins. On completion,the mixture was concentrated in vacuo to give the title compound (300mg, 99% yield) as yellow oil. LC-MS (ESI⁺) m/z 374.2 (M+H)⁺.

Tert-Butyl N-hex-5-ynyl-N-methyl-carbamate (Intermediate GM)

Step 1—Hex-5-vnvl methanesulfonate

To a solution of hex-5-yn-1-ol (2.00 g, 20.4 mmol, CAS #928-90-5) andTEA (5.16 g, 51.0 mmol) in DCM (20 mL) was added MsCl (2.80 g, 24.5mmol) at 0° C. The reaction mixture was stirred at 0° C. for 3 hrs. Oncompletion, the mixture was quenched with water (20 mL), and extractedwith DCM (2×20 mL). The organic layer was washed with brine (50 mL),dried with Na₂SO₄, filtered and the filtrate was concentrated in vacuoto give the title compound (3.20 g, 89% yield) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 4.27 (t, J=6.4 Hz, 2H), 3.02 (s, 3H), 2.30-2.24 (m,2H), 1.98 (t, J=2.8 Hz, 1H), 1.93-1.84 (m, 2H), 1.70-1.64 (m, 2H).

Step 2—N-methylhex-5-yn-1-amine

A solution of hex-5-ynyl methanesulfonate (0.60 g, 3.40 mmol) and KI(28.3 mg, 170 umol) in a solution of methanamine (2 M, 8.51 mL) wasstirred at 55° C. for 15 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (0.25 g, 66% yield) asyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 2.63 (t, J=7.2 Hz, 2H), 2.45 (s,3H), 2.23-2.19 (m, 2H), 1.94 (t, J=2.4 Hz, 1H), 1.68-1.56 (m, 4H).

Step 3—Tert-Butyl N-hex-5-ynyl-N-methyl-carbamate

To a solution of N-methylhex-5-yn-1-amine (500 mg, 4.50 mmol) in MeOH(10 mL) was added (Boc)₂O (1.18 g, 5.40 mmol). The reaction mixture wasstirred at 25° C. for 17 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (670 mg, 70% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.22-3.11 (m, 2H), 2.77 (s,3H), 2.20-2.12 (m, 2H), 1.88 (t, J=2.4 Hz, 1H), 1.60-1.53 (m, 2H),1.46-1.41 (m, 2H), 1.39 (s, 9H).

2-(2,6-Dioxo-3-piperidyl)-4-[6-(methylamino)hexyl]isoindoline-1,3-dione(Intermediate GN)

Step 1—Tert-ButylN-[6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]hex-5-ynyl]-N-methyl-carbamate

4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.60 g, 1.78mmol, Intermediate FT), CuI (33.9 mg, 178 umol) and Pd(PPh₃)₂Cl₂ (125mg, 178 umol) was taken up into a microwave tube. Then tert-butylN-hex-5-ynyl-N-methyl-carbamate (602 mg, 2.85 mmol, Intermediate GM),TEA (3.24 g, 32.0 mmol) and DMF (5 mL) were added into the above tube.The mixture was degassed with N₂ gas for 5 minutes. The sealed tube washeated at 80° C. for 30 minutes under microwave. On completion, themixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by reverse phase (0.1% HCl condition) to give thetitle compound (720 mg, 78% yield) as a yellow gum. LC-MS (ESI⁺) m/z490.1 (M+Na)⁺.

Step 2—Tert-ButylN-[6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]hexyl]-N-methyl-carbamate

To a solution of tert-butylN-[6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]hex-5-ynyl]-N-methyl-carbamate(720 mg, 1.39 mmol) in THF (8 mL) was added Pd/C (0.2 g, 10 wt %) andPd(OH)₂/C (0.2 g, 10 wt %). The reaction mixture was stirred at 25° C.for 18 hrs under H₂ (15 Psi). On completion, the mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(620 mg, 95% yield) as a light yellow solid. LC-MS (ESI⁺) m/z 494.1(M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-4-[6-(methylamino)hexyl]isoindoline-1,3-dione

To a solution of tert-butylN-[6-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]hexyl]-N-methyl-carbamate(620 mg, 1.31 mmol) in DCM (4 mL) was added HCl/dioxane (6 mL). Thereaction mixture was stirred at 25° C. for 0.5 hr. On completion, themixture was concentrated in vacuo to give the title compound (530 mg,94% yield) as a yellow solid. LC-MS (ESI⁺) m/z 372.2 (M+H)⁺.

4-(3-Aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Intermediate GO)

Step 1—Tert-Butyl(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)prop-2-yn-1-yl)carbamate

4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (200 mg, 593umol, Intermediate FT), tert-butyl N-prop-2-ynylcarbamate (CAS #:92136-39-5) (92.0 mg, 593 umol), Pd(PPh₃)₂Cl₂ (41.6 mg, 59.3 umol) andTEA (1.08 g, 10.7 mmol, 1.49 mL), CuI (11.3 mg, 59.3 umol) were taken upinto a microwave tube in DMF (3 mL) under N₂. The reaction mixture wasde-gassed with N₂ and then the seal tube was heated to 80° C. for 0.5hour. On completion, the reaction mixture was concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE:EA=2:1) to givethe title compound (200 mg, 73% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.07 (s, 1H), 7.85 (dd, J=1.2, 7.2 Hz, 1H), 7.78-7.69 (m,2H), 5.01 (dd, J=5.2, 12.4 Hz, 1H), 4.94 (s, 1H), 4.28 (d, J=5.2 Hz,2H), 2.94-2.74 (m, 3H), 2.21-2.14 (m, 1H), 1.50 (s, 9H); LC-MS (ESI⁺)m/z 434.0 (M+Na)⁺.

Step 2—Tert-Butyl(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propyl)carbamate

To a solution of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynyl]carbamate (200 mg, 433 umol) in THF (20 mL) was added Pd/C (20 mg, 10%wt) and Pd(OH)₂/C (20 mg, 10% wt) under N₂. The suspension was degassedunder vacuum and purged with H₂ gas several times. The mixture wasstirred under H₂ (15 Psi) at 25° C. for 12 hours. On completion, thereaction mixture was filtered and concentrated in vacuo to give thetitle compound (200 mg, 95% yield) as a white solid. LC-MS (ESI⁺) m/z438.0 (M+Na)⁺.

Step3—4-(3-Aminopropyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propyl]carbamate(200 mg, 404 umol) in DCM (5 mL) was added HC/dioxane (4 M, 5 mL). Themixture was stirred at 25° C. for 1 hour. On completion, the reactionmixture was concentrated in vacuo to give the title compound (142 mg,100% yield) as a white solid.

Tert-Butyl(4-(4-((3-carbamoyl-1-(4-(methyl(5-oxopentvl)carbamoyl)phenyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(cyclopropylmethyl)carbamate(Intermediate GP)

Step 1—Tert-Butyl(4-(4-((3-carbamoyl-1-(4-((5-hydroxypentyl)(methyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(cyclopropylmethyl)carbamate

To a solution of 5-(methylamino)pentan-1-ol (141 mg, 918 umol, HCl,synthesized via Steps 1-2 of Intermediate GI) and4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (539 mg, 918 umol, Intermediate DF) in DMF (25 mL) was added DIPEA(593 mg, 4.59 mmol, 799 uL). The reaction mixture was stirred at 0.5hour. Then HATU (384 mg, 1.01 mmol) was added to the reaction mixture.The resulting reaction mixture was stirred at 25° C. for 0.5 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give theresidue. The residue was purified by prep-HPLC (acidified condition:0.1%, HCl) to give the title compound (300 mg, 48% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 10.97 (s, 1H), 8.91 (s, 1H), 8.58-8.49(m, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.84 (d, J=8.8 Hz, 2H), 7.79 (dd,J=1.2, 5.2 Hz, 1H), 7.62-7.54 (m, 2H), 6.91 (s, 1H), 5.58 (s, 1H), 3.95(d, J=7.2 Hz, 2H), 3.73-3.71 (m, 1H), 3.63-3.61 (m, 2H), 3.33-3.31 (m,1H), 1.75-1.59 (m, 2H), 1.59 (s, 9H), 1.54-1.50 (m, 2H), 1.31-1.18 (m,3H), 0.50-0.40 (m, 2H), 0.34-0.25 (m, 2H).

Step 2—Tert-Butyl(4-(4-((3-carbamoyl-1-(4-(methyl(5-oxopentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(cyclopropylmethyl)carbamate(9)—Notebook Page: EW5356-822

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[5-hydroxypentyl(methyl)carbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(300 mg, 437 umol) in DCM (10 mL) was added DMP (371 mg, 874 umol, 270uL). The reaction mixture was stirred at 25° C. for 5 hrs. Oncompletion, the reaction mixture was quenched with saturated NaS₂O₃ (30mL), and extracted with DCM (3×100 mL). The combined organic layer waswashed with saturated NaHCO₃ (50 mL), then washed with brine (50 mL),dried over anhydrous sodium sulfate, filtered and concentrated in vacuoto give the title compound (299 mg, 100% yield) as a white solid. LC-MS(ESI⁺) m/z 685.1 (M+H)⁺.

Tert-Butyl N-tert-butoxycarbonyl-N-non-8-ynyl-carbamate (IntermediateGO)

Step 1—Non-8-ynyl methanesulfonate

To a mixture of non-8-yn-1-ol (5.00 g, 35.6 mmol, CAS #10160-28-8) andTEA (10.8 g, 106 mmol, 14.8 mL) in DCM (100 mL) was added MsCl (6.13 g,53.4 mmol, 4.14 mL). The reaction mixture was stirred at 25° C. for 2hours. On completion, the reaction mixture was concentrated in vacuo.The residue was diluted with water (10 mL) and extracted with DCM (3×10mL). The combined organic layers was dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (7.70 g, 98% yield) aslight yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.23 (t, J=6.4 Hz, 2H), 3.01(s, 3H), 2.22-2.18 (m, 2H), 1.95 (t, J=2.4 Hz, 1H), 1.80-1.73 (m, 2H),1.58-1.50 (m, 2H), 1.47-1.36 (m, 6H).

Step 2—Tert-Butyl N-tert-butoxvcarbonyl-N-non-8-vnvl-carbamate

To a mixture of non-8-ynyl methanesulfonate (1.00 g, 4.58 mmol) andtert-butyl N-tert-butoxycarbonylcarbamate (1.49 g, 6.87 mmol, CAS#51779-32-9) in ACN (10 mL) was added Cs₂CO₃ (4.48 g, 13.7 mmol). Thereaction mixture was stirred at 80° C. for 2 hours. On completion, thereaction mixture was filtered and concentrated in vacuo. The residue waspurified by column chromatography to give the title compound (650 mg,41% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.59-3.53 (m,2H), 2.22-2.12 (m, 2H), 1.94 (t, J=2.4 Hz, 1H), 1.62-1.53 (m, 4H), 1.52(s, 18H), 1.45-1.29 (m, 6H).

Tert-Butyl N-methyl-N-non-8-ynyl-carbamate (Intermediate GR)

To a solution of tert-butyl N-methylcarbamate (300 mg, 2.29 mmol, CAS#16066-84-5) in DMF (10 mL) was added NaH (183 mg, 4.58 mmol, 60%purity) at 0° C. The mixture was stirred at 25° C. for 2 hours. Thennon-8-ynyl methanesulfonate (0.5 g, 2.29 mmol, synthesized via Step 1 ofIntermediate GQ) in dry DMF (2 mL) was added at 0° C., and then themixture was stirred at 25° C. for 5 hours. On completion, the mixturewas quenched by addition H₂O (30 mL), then extracted with EA (3×50 mL),and the organic phase was concentrated in vacuo to give a residue. Theresidue was purified by flash silica gel chromatography to give thetitle compound (410 mg, 70% yield) as colorless oil. ¹H NMR (400 MHz,DMSO-d₆) δ 3.14 (t, J=7.6 Hz, 2H), 2.75 (s, 3H), 2.74-2.72 (m, 1H),2.17-2.11 (m, 2H), 1.48-1.42 (m, 4H), 1.39 (s, 9H), 1.35-1.18 (m, 6H).

2-(2,6-Dioxo-3-piperidyl)-4-[9-(methylamino)nonyl]isoindoline-1,3-dione(Intermediate GS)

Step 1—Tert-ButylN-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]non-8-ynyl]-N-methyl-carbamate

4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (300 mg, 889umol, Intermediate FT), CuI (16.9 mg, 88.9 umol) and Pd(PPh₃)₂Cl₂ (62.4mg, 88.9 umol) were taken up into a microwave tube. Then tert-butylN-methyl-N-non-8-ynyl-carbamate (405 mg, 1.60 mmol, Intermediate GR),TEA (1.62 g, 16.0 mmol, 2.23 mL) and DMF (3 mL) were added into theabove tube. The mixture was degassed with N₂ for 5 minutes. The sealedtube was heated at 80° C. for 30 minutes under microwave. On completion,the mixture was concentrated in vacuo to give a residue. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(380 mg, 77% yield) as a white solid. LC-MS (ESI⁺) m/z 532.4 (M+Na)⁺.

Step 2—Tert-ButylN-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]nonyl]-N-methyl-carbamate

To a solution of tert-butylN-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]non-8-ynyl]-N-methyl-carbamate(380 mg, 745 umol) in THF (10 mL) was added Pd(OH)₂/C (100 mg, 10 wt %)and Pd/C (100 mg, 10 wt %). The reaction mixture was stirred under H₂(15 psi) at 25° C. for 12 hours. On completion, the residue was filteredand the filtrate was concentrated in vacuo to give the title compound(380 mg, 99% yield) as yellow oil. LC-MS (ESI⁺) m/z 536.2 (M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-4-[9-(methylamino)nonyl]isoindoline-1,3-dione

To a solution of tert-butylN-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]nonyl]-N-methyl-carbamate(380 mg, 739 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 4 mL), andthe reaction mixture was stirred at 25° C. for 20 min. On completion,the mixture was concentrated in vacuo to give the title compound (330mg, 99% yield, HCl) as yellow solid. LC-MS (ESI⁺) m/z 414.3 (M+H)⁺.

4-(9-Aminononyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate GT)

Step 1—Tert-ButylN-tert-butoxycarbonyl-N-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]non-8-ynyl]carbamate

To a mixture of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(300 mg, 889 umol, Intermediate FT) and tert-butylN-tert-butoxycarbonyl-N-non-8-ynyl-carbamate (453 mg, 1.33 mmol,Intermediate GQ) in DMF (5 mL) was added Pd(PPh₃)₂Cl₂ (62.4 mg, 88.9umol), CuI (16.9 mg, 88.9 umol) and TEA (1.62 g, 16.0 mmol, 2.23 mL).The reaction mixture was heated at 80° C. for 30 mins under microwave.On completion, the reaction mixture was concentrated in vacuo. Theresidue was purified by prep-HPLC (0.1% FA condition) compound (340 mg,64% yield) as brown oil. LC-MS (ESI⁺) m/z 618.4 (M+Na)⁺.

Step 2—Tert-ButylN-tert-butoxycarbonyl-N-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]nonyl]carbamate

To a mixture of tert-butylN-tert-butoxycarbonyl-N-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]non-8-ynyl]carbamate(440 mg, 738 umol) in THF (5 mL) was added Pd/C (150 mg, 10 wt %) andPd(OH)₂/C (150 mg, 10 wt %). The reaction mixture was stirred at 25° C.for 1 hour under H₂ (15 Psi) atmosphere. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (442 mg, 99% yield) as white solid. LC-MS (ESI⁺) m/z 622.5(M+Na)⁺.

Step 3—4-(9-Aminononyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-tert-butoxycarbonyl-N-[9-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]nonyl]carbamate(442 mg, 737 umol) in DCM (3 mL) was added HC/dioxane (4 M, 5 mL). Thereaction mixture was stirred at 25° C. for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(320 mg, 99% yield, HCl) as colourless oil. LC-MS (ESI⁺) m/z 400.3(M+H)⁺.

3-[4-[3-(2-aminoethoxy)propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(Intermediate GU)

Step 1—Tert-Butyl(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate

To a stirred solution of3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.5 g, 1.551 mmol,Intermediate IR) in DMF (6.0 ml) was added tert-butyl(2-(prop-2-yn-1-yloxy)ethyl)carbamate (0.46 g, 2.32 mmol, IntermediateIU) at rt. The reaction mixture was purged with N₂ gas for 20 min. Tothis stirred reaction mixture were added CuI (0.014 g, 0.077 mmol), TEA(6.0 ml, 36.09 mmol), PdCl₂(PPh₃)₂ (0.054 g, 0.0776 mmol) and themixture was further purged with N₂ gas for 20 min. The reaction mixturewas heated at 80° C. for 3 h. The reaction mixture was then poured intowater (100 ml) and the product was extracted with ethyl acetate (3×100ml). The combined organic layer dried over anhydrous Na₂SO₄, filteredand concentrated under vacuum to afford tert-butyl(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate(0.28 g, 0.64 mmol). LCMS m/z: ES+ 386.17 (M−55)⁺.

Step 2—Tert-Butyl(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethyl)carbamate

To a solution of tert-butyl(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate(1.5 g, 3.40 mmol) in methanol (50 ml) was added 10 wt % Pd/C (0.2 g) atrt. Hydrogen gas was purged in to the reaction mixture at rt for 4 h.The resulting reaction mixture was filtered over a bed of celite andwashed with methanol (50 ml). The obtained filtrate was concentratedunder vacuum. The crude material was purified by silica gel flashchromatography (eluting at 4% MeOH in MDC) to afford tert-butyl(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethyl)carbamate(0.6 g, 1.34 mmol). LCMS m/z: ES+ 346.2 (M−99)⁺. ¹H NMR (400 MHz,DMSO-d6) δ 11.01 (s, 1H), 7.58 (dd, J=5.0, 3.6 Hz, 1H), 7.49-7.45 (m,2H), 6.80 (t, J=5.7 Hz, 1H), 5.15 (dd, J=13.2, 5.1 Hz, 1H), 4.47 (d,J=17.2 Hz, 1H), 4.31 (d, J=17.1 Hz, 1H), 3.38 (dd, J=12.9, 6.4 Hz, 7H),3.08 (q, J=6.0 Hz, 2H), 2.94 (ddd, J=17.3, 13.7, 5.4 Hz, 1H), 2.69 (dd,J=8.9, 6.5 Hz, 2H), 2.66-2.56 (m, 1H), 2.42 (td, J=13.2, 4.5 Hz, 1H),2.02 (dtd, J=12.6, 5.3, 2.3 Hz, 1H), 1.83 (p, J=6.8 Hz, 2H), 1.37 (s,9H).

Step3—3-(4-(3-(2-aminoethoxv)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]propoxy]ethyl]carbamate (200 mg, 448 umol) in DCM (2.00 mL) was addedHCl/dioxane (4 M, 2.00 mL). The mixture was stirred at 20° C. for 0.5hour. On completion, the mixture was concentrated in vacuo to give thetitle compound (170 mg, 80% yield, HCl) as yellow solid. LC-MS (ESI⁺)m/z 346.3 (M+H)⁺.

3-[3-[2-[2-(2-aminoethoxy)ethoxyl]ethyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate GV)

Step 1: Tert-Butyl(2-(2-(2-((2-nitrophenvl)amino)ethoxv)ethoxy)ethyl)carbamate

To a solution of tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate(15.0 g, 0.060 mol, CAS #153086-78-3) in DMF (30 mL) was added1-fluoro-2-nitrobenzene (10.2 g, 0.072 mmol), and K₂CO₃ (25.1 g, 0.182mmol) at r.t. The reaction was heated at 60° C. for 3 h. The mixture wasquenched with water and extracted with EtOAc (100 ml×2). The combinedorganic layer was washed with brine, dried and concentrated in vacuo.The residue was purified via column chromatography (petroleumether/EtOAc=5%-80%) to give the desired compound (12.8 g, 57% yield) asa yellow oil. LC-MS (ESI⁺): m/z 370.2 (M+H)⁺.

Step 2: Tert-Butyl(2-(2-(2-((2-aminophenyl)amino)ethoxy)ethoxy)ethyl)carbamate

To a solution of tert-butyl(2-(2-(2-((2-nitrophenyl)amino)ethoxy)ethoxy)ethyl)carbamate (12.8 g,34.7 mmol) in MeOH (200 mL) was added Pd/C (720 mg) at r.t. The reactionmixture was degassed and purged with hydrogen three times. The reactionwas stirred at r.t. for 12 hs under hydrogen. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo to give thedesired compound (11.2 g, 95% yield) as a yellow oil. LC-MS (ESI⁺): m/z340.2 (M+H)⁺.

Step 3: Tert-Butyl(2-(2-(2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)carbamate

To a solution of tert-butyl(2-(2-(2-((2-aminophenyl)amino)ethoxy)ethoxy)ethyl)carbamate (11.2 g,33.04 mmol) in THF (100 mL) was added CDI (6.5 g, 40.37 mmol) at r.t.The reaction was stirred at r.t. overnight. The mixture was quenchedwith water and extracted with EtOAc (100 ml×2). The combined organiclayer was washed with brine, dried and concentrated in vacuo. Theresidue was purified via column chromatography (petroleumether/EtOAc=5%-80%) to give the desired compound (3.7 g, 31% yield) as ayellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.84 (s, 1H), 7.20-7.13(m, 1H), 7.03-6.94 (m, 3H), 6.75 (t, J=5.5 Hz, 1H), 3.94 (t, J=5.7 Hz,2H), 3.66 (t, J=5.7 Hz, 2H), 3.51 (d, J=5.3 Hz, 2H), 3.44 (d, J=5.2 Hz,2H), 3.32 (t, J=6.1 Hz, 2H), 3.02 (q, J=5.9 Hz, 2H), 1.37 (s, 9H).

Step 4: Tert-Butyl(2-(2-(2-(3-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)carbamate

To a stirred solution of tert-butyl(2-(2-(2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)carbamate(1.5 g, 4.12 mmol) in THF (300 ml) was added t-BuOK (370 mg, 3.3 mol) atroom temperature portion-wise. After addition, the mixture was stirredat room temperature for 2 h. Then the3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (1.9 g, 6.16 mmol) inTHF (20 ml) was added dropwise. The mixture was stirred at roomtemperature for 2 h. Then a second batch of t-BuOK (370 mg, 3.3 mmol)was added portion-wise, and the mixture was stirred for an additional 30min. Then the mixture was poured into water, and extracted with EtOAc(3×200 ml). The combined organic layers were concentrated under reducedpressure, and the residue was purified by column on silica gel elutingwith EtOAc:DCM=2:1 to get the title compound (600 mg, 24% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.36 (m, J=8.50 Hz, 2H),7.17 (d, J=7.75 Hz, 1H), 7.08 (t, J=7.75 Hz, 1H), 6.94 (t, J=7.75 Hz,1H), 6.83 (m, J=8.38 Hz, 2H), 6.50 (d, J=7.88 Hz, 1H), 5.23 (dd,J=13.13, 5.38 Hz, 1H), 4.96 (d, J=2.00 Hz, 2H), 4.09 (t, J=5.63 Hz, 2H),3.74-3.86 (m, 5H), 3.57-3.62 (m, 2H), 3.51-3.56 (m, 2H), 3.41-3.49 (m,2H), 3.21-3.29 (m, 2H), 2.95-3.07 (m, 1H), 2.77-2.89 (m, 1H), 2.54-2.68(m, 1H), 2.13-2.22 (m, 1H), 1.46 (s, 9H). LC-MS (ESI⁺): m/z 597.0(M+H)⁺.

Step 5:3-(3-(2-(2-(2-aminoethoxv)ethoxv)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl(2-(2-(2-(3-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethoxy)ethoxy)ethyl)carbamate(640 mg, 1.074 mmol) in toluene (5 mL) was added MsOH (2.1 g, 21 mmol).The reaction was heated at 110° C. for 3 h. The reaction mixture wascooled to room temperature, then concentrated under reduced pressure.The residue was poured into ice water, then basified with sat. NaHCO₃ topH=7-8. Then the mixture was purified by prep HPLC eluting with ACN/H₂O(0.10% HCOOH)=0%-10% to give the desired formic acid salt compound as acolorless oil (62 mg, 15% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 7.33(d, J=7.38 Hz, 1H), 7.01-7.24 (m, 3H), 5.45 (dd, J=12.57, 5.07 Hz, 1H),4.27-4.54 (m, 2H), 4.04-4.13 (m, 2H), 3.68-3.86 (m, 2H), 3.61 (br. s.,2H) 3.34-3.58 (m, 4H), 2.89-3.03 (m, 1H), 2.63-2.84 (m, 2H), 1.98-2.18(m, 1H) LC-MS (ESI⁺): m/z 377.0 (M+H)⁺.

4-[3-(2-Aminoethoxv)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate GW)

Step 1—Tert-ButylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethyl]carbamate

To a solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1.95 g, 5.79 mmol, Intermediate FT) and tert-butylN-(2-prop-2-ynoxyethyl)carbamate (1.50 g, 7.53 mmol, synthesized viaStep 1 on Intermediate CP) in DMF (10 mL) was added Pd(PPh₃)₂Cl₂ (406mg, 579 umol), TEA (10.5 g, 104 mmol) and CuI (110 mg, 579 umol). Themixture was heated at 80° C. for 30 minutes under microwave. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatography(PE:EA=1:1) to give the title compound (1.80 g, 68% yield) as lightyellow oil; LC-MS (ESI⁺) m/z 478.0 (M+Na)⁺.

Step 2—Tert-ButylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethyl]carbamate (1.00 g, 2.20 mmol) in THF (30 mL) was added Pd/C (0.2g, 10% w/w) and Pd(OH)₂/C (0.2 g, 10% w/w) under N₂. The suspension wasdegassed under vacuum and purged with H₂ gas three times. The mixturewas stirred under H₂ (15 Psi) at 20° C. for 1 hour. On completion, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give title compound (600 mg, 60% yield) as white solid; LC-MS (ESI⁺)m/z 482.2 (M+Na)⁺.

Step3—4-[3-(2-Aminoethoxy)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(7)—Notebook Page: EW5417-748

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethyl]carbamate (200 mg, 435 umol) in DCM (2 mL) was added HCl/dioxane(4 M, 0.8 mL). The mixture was stirred at 20° C. for 2 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (156 mg, 90% yield, HCl salt) as white solid; LC-MS(ESI⁺) m/z 360.1 (M+H)⁺.

4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate GX)

Step 1—Tert-ButylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate

To a solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1 g, 2.97 mmol, Intermediate FT) and tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (1.44 g, 5.93 mmol,synthesized via Step 1 of Intermediate CQ) in DMF (8 mL) was addedPd(PPh₃)₂Cl₂ (208 mg, 296 umol), TEA (5.4 g, 53.3 mmol, 7.43 mL) and CuI(56.4 mg, 296 umol). The reaction mixture was heated at 80° C. for 30min under microwave. On completion, the mixture was concentrated invacuo to give a residue. The residue was purified by columnchromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to I/O, Rf=0.73)to give the title compound (1.20 g, 72% yield) as yellow solid. LC-MS(ESI⁺) m/z 500.1 (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2—ynoxy]ethoxy]ethyl]carbamate(600 mg, 1.20 mmol) in THF (10 mL) was added Pd/C (300 mg, 1.20 mmol, 10wt %) and Pd(OH)₂/C (300 mg, 1.20 mmol, 10 wt %). The reaction mixturewas stirred at 25° C. under H₂ (15 psi) for 12 hours. On completion, theresidue was filtered and the filtrate was concentrated in vacuo to givethe title compound (600 mg, 99% yield) as yellow oil. LC-MS (ESI⁺) m/z526.4 (M+Na)⁺.

Step3—4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethyl]carbamate (600 mg, 1.19 mmol) in DCM (2 mL) was addedHCl/dioxane (4 M, 2.00 mL), and the reaction mixture was stirred at 25°C. for 20 minutes. On completion, the mixture was concentrated in vacuoto give the title compound (500 mg, 95% yield) as yellow solid. LC-MS(ESI⁺) m/z 404.3 (M+H)⁺.

Tert-ButylN-[4-[-[[3-carbamoyl-1-(4-formylphenvl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate GY)

Tert-butylN-[4-[4-[[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamatewas synthesized as described below in Step 1 of Example 171.

Tert-ButylN-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]carbamate(Intermediate GZ)

To a solution of tert-butylN-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (2.00 g, 6.82mmol, synthesized via Steps 1-3 of Intermediate AO) and3-bromoprop-1-yne (973 mg, 8.18 mmol, 705 uL) in THF (30 mL) was addedTBAI (151 mg, 409 umol), KI (169 mg, 1.02 mmol), KOH (382 mg, 6.82mmol). The reaction mixture was stirred at 25° C. for 16 hours. Oncompletion, the mixture was filtered, and the filterate was concentratedin vacuo to give a residue. The residue was purified by flash silica gelchromatography to give the title compound (0.85 g, 37% yield) as yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 5.06 (s, 1H), 4.21 (d, J=2.4 Hz, 2H),3.72-3.61 (m, 14H), 3.54 (t, J=5.2 Hz, 2H), 2.46-2.43 (m, 1H), 1.45 (s,9H).

4-[3-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate HA)

Step 1—Tert-ButylN-[2-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]carbamate (690 mg,2.08 mmol, Intermediate GZ) and4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (540 mg, 1.60mmol, Intermediate FT) in DMF (6 mL) was added Pd(PPh₃)₂Cl₂ (112 mg, 160umol), CuI (30.5 mg, 160 umol) and TEA (2.92 g, 28.8 mmol, 4.01 mL). Thereaction mixture was heated at 80° C. for 30 minutes under microwave. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% FA condition) to give the title compound(580 mg, 61% yield) as light yellow oil. LC-MS (ESI⁺) m/z 610.4 (M+Na)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxylethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (380 mg, 646 umol) inTHF (10 mL) was added Pd(OH)₂/C (150 mg, 10 wt %) and Pd/C (150 mg, 10wt %). The reaction mixture was stirred at 25° C. for 0.5 hour under H₂(15 Psi) atmosphere. On completion, the reaction mixture was filteredand concentrated in vacuo to give the title compound (382 mg, 99% yield)as light yellow oil. LC-MS (ESI⁺) m/z 592.3 (M+H)⁺.

Step3—4-[3-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[2-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (382 mg, 645 umol) in DCM(3 mL) was added HC/dioxane (4 M, 5 mL). The reaction mixture wasstirred at 25° C. for 1 hour. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (340 mg, 99% yield,HCl) as light yellow oil. LC-MS (ESI⁺) m/z 492.3 (M+H)⁺.

3-[4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(Intermediate HB)

Step1—(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn1yl)oxv)ethoxv)ethyl)carbamate

To a stirred solution of3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.3 g, 0.93 mmol,Intermediate IR) in DMF (6.0 ml) was added tert-butyl(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl) carbamate (0.34 g, 1.39 mmol,Intermediate IT) at rt. The reaction mixture was purged with N₂ gas for20 min. To this stirred reaction mixture were added CuI (0.008 g, 0.0465mmol), TEA (3.2 ml, 22.35 mmol), PdCl₂(PPh₃)₂ (0.032 g, 0.0465 mmol) andthe reaction was further purged with N₂ gas for 20 min. Then thereaction mixture was heated at 80° C. for 3 h. On completion, thereaction mixture was poured into water (100 ml) and product wasextracted with ethyl acetate (3×100 ml). The combined organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. Thecrude material was purified by silica gel flash chromatography (elutingat 3% MeOH in MDC) to afford tert-butyl(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate (0.2 g, 0.412 mmol). LCMS m/z: (ES+) 508.2 (M+23)⁺.

Step 2—Tert-Butl(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethoxy)ethyl)lcarbamate

To a solution of tert-butyl(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(1.4 g, 2.88 mmol) in methanol (50 ml) was added 10 wt % Pd/C (0.2 g) atrt. Hydrogen gas was purged in to the reaction mixture at rt for 4 h.The resulting reaction mixture was filtered over a bed of celite andwashed with methanol (50 ml). The obtained filtrate was concentratedunder vacuum. The obtained crude material was purified by silica gelchromatography (eluting at 4% MeOH in MDC) to afford tert-butyl(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethoxy)ethyl)carbamate (0.8 g, 1.63 mmol). LCMS m/z: ES+ 390.3 (M−99)⁺. ¹H NMR (400MHz, DMSO-d6) δ 11.02 (s, 1H), 7.58 (dd, J=5.3, 3.3 Hz, 1H), 7.51-7.42(m, 2H), 5.15 (dd, J=13.3, 5.0 Hz, 1H), 4.47 (d, J=17.2 Hz, 1H), 4.30(d, J=17.1 Hz, 1H), 3.49 (td, J=5.2, 2.9 Hz, 3H), 3.38 (dd, J=7.0, 4.4Hz, 6H), 3.06 (q, J=6.1 Hz, 2H), 3.00-2.86 (m, 1H), 2.70 (d, J=7.8 Hz,2H), 2.61 (d, J=17.6 Hz, 2H), 2.42 (d, J=4.5 Hz, 1H), 2.01 (dd, J=9.4,3.7 Hz, 1H), 1.84 (t, J=7.5 Hz, 2H), 1.36 (d, J=4.6 Hz, 9H).

Step3—3-(4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]propoxy]ethoxy]ethyl]carbamate (200 mg, 408 umol) in DCM (3 mL) was added HCl/dioxane(4 M, 4 mL). The mixture was stirred at 20° C. for 2 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (155 mg, 89% yield) as yellow solid. LC-MS (ESI⁺) m/z390.1 (M+H)⁺.

3-[4-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(Intermediate HC)

Step 1—Tert-Butyl(2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate

To a stirred solution of3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (0.5 g, 1.55 mmol,Intermediate IR) in DMF (6.0 ml) was added tert-butyl(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate (0.6 g, 2.32mmol, Intermediate IS) at rt. The reaction mixture was purged with N₂gas for 20 min. To the stirred reaction mixture were added CuI (0.014 g,0.0776 mmol), TEA (5.5 ml, 37.26 mmol), PdCl₂(PPh₃)₂ (0.054 g, 0.0776mmol) and further purged with N₂ gas for 20 min. The reaction mixturewas heated at 80° C. for 3 h. On completion, the reaction mixture waspoured into water (200 ml) and product was extracted with ethyl acetate(3×200 ml). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated under vacuum. The crude material was purifiedby silica gel flash chromatography (eluting at 4% MeOH in MDC) to affordtert-butyl(2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate(0.5 g, 1.0 mmol). LCMs m/z: (ES+) 528.4 (M−1)⁺.

Step 2—tert-butyl(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethoxy)ethyl)carbamate

To a solution of tert-butyl(2-(2-(2-((3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate(1.5 g, 2.83 mmol) in methanol (50 ml) was added 10 wt % Pd/C (0.15 g)at rt. Hydrogen gas was purged into the reaction mixture at rt for 4 h.The resulting reaction mixture was filtered over a bed of celite andwashed with methanol (50 ml). The obtained filtrate was concentratedunder vacuum. The crude material was purified by combi flashchromatography (eluting at 4% MeOH in MDC) to afford tert-butyl(2-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)propoxy)ethoxy)ethyl)carbamate (0.3 g, 0.56 mmol). LCMS m/z: (ES+) 390.3 (M−99)⁺. ¹H NMR (400MHz, DMSO-d6) δ 11.03 (s, 1H), 7.58 (dd, J=5.6, 3.0 Hz, 1H), 7.49-7.44(m, 2H), 6.78 (t, J=5.8 Hz, 1H), 5.15 (dd, J=13.3, 5.1 Hz, 1H), 4.47 (d,J=17.1 Hz, 1H), 4.30 (d, J=17.2 Hz, 1H), 3.50 (tq, J=8.2, 2.8 Hz, 8H),3.05 (q, J=6.0 Hz, 3H), 2.94 (ddd, J=17.2, 13.6, 5.4 Hz, 1H), 2.74-2.63(m, 3H), 2.59 (s, 3H), 2.41 (td, J=13.2, 4.5 Hz, 1H), 2.05-1.92 (m, 1H),1.91-1.77 (m, 2H), 1.37 (d, J=4.5 Hz, 9H).

Step3—3-[4-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]propyl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate(200 mg, 374 umol) in DCM (2.00 mL) was added HCl/dioxane (4 M, 4.00mL). The mixture was stirred at 15° C. for 0.5 hr. On completion, themixture was concentrated in vacuo to give the title compound (170 mg,80% yield) as yellow solid. LC-MS (ESI⁺) m/z 434.3 (M+H)⁺.

1-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide(Intermediate HD)

Step 1—Tert-ButylN-[2-[2-[2-[2-(3-carbamoyl-4-nitro-pyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (6.50 g, 17.5 mmol, Intermediate AO),4-nitro-1H-pyrazole-3-carboxamide (2.48 g, 15.9 mmol, Intermediate CJ)in DMF (80.0 mL) was added Cs₂CO₃ (10.3 g, 31.8 mmol). The mixture wasstirred at 130° C. for 16 hours. On completion, the mixture was filteredand the organic layer was concentrated in vacuo. The mixture waspurified by reverse phase (0.10% FA) to give the title compound (2.00 g,29% yield) as yellow solid. LC-MS (ESI⁺) m/z 454.3 (M+Na)⁺.

Step2—1-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide

To a solution oftert-butylN-[2-[2-[2-[2-(3-carbamoyl-4-nitro-pyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.00 g, 2.32 mmol) in DCM (3.00 mL) was addedHCl/dioxane (4 M, 5.00 mL). The mixture was stirred at 15° C. for 0.5hour. On completion, the mixture was concentrated in vacuo to give thetitle compound (500 mg, 80% yield, HCl) as yellow oil. ¹H NMR (400 MHz,MeOD-d₄) δ 8.64 (s, 1H), 4.41-4.38 (m, 2H), 3.90-3.87 (m, 2H), 3.68-3.65(m, 4H), 3.62-3.60 (m, 6H), 3.13-3.09 (m, 2H).

4-Amino-1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]pyrazole-3-carboxamide(Intermediate HE)

Step1—1-[2-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxyethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide

To a solution of1-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide(300 mg, 815 umol, HCl, Intermediate HD),2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (247 mg, 897umol, Intermediate R) in dioxane (5.00 mL) was added DIPEA (1.05 g, 8.16mmol), and the mixture was stirred at 115° C. for 16 hours. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by silica gel column (DCM:MeOH=30:1) to give the title compound(100 mg, 20% yield) as yellow oil. LC-MS (ESI⁺) m/z 588.3 (M+H)⁺.

Step2—4-Amino-1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxylethoxy]ethoxy]ethyl]pyrazole-3-carboxamide

To a solution of1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]-4-nitropyrazole-3-carboxamide (70.0 mg, 119 umol)in THF (5.00 mL) was added Pd/C (25.0 mg), and the mixture was stirredat 15° C. for 15 min under H₂ (15 psi). On completion, the mixture wasfiltered. The filtrate was concentrated in vacuo to give the titlecompound (60.0 mg, 90% yield) as yellow solid. LC-MS (ESI⁺) m/z 558.2(M+H)⁺.

4-Amino-1-(2-hydroxvethyl)pyrazole-3-carboxamide (Intermediate HF)

Step 1—Ethyl 2-(3-carbamoyl-4-nitro-pyrazol-1-yl)acetate

To a solution of 4-nitro-1H-pyrazole-3-carboxamide (1.5 g, 9.61 mmol,Intermediate CJ) and ethyl 2-bromoacetate (1.68 g, 10.0 mmol) in DMF (20mL) was added Cs₂CO₃ (3.13 g, 9.61 mmol), the mixture was stirred at 20°C. for 16 hours. On completion, the mixture was filtered to give thefiltrate and concentrated in vacuo to give a residue. The residue waspurified by silica gel chromatography to give the title compound (1.60g, 68% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (s, 1H),8.05 (s, 1H), 7.78 (s, 1H), 5.19 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 1.23(t, J=7.2 Hz, 3H).

Step 2—Ethyl 2-(4-amino-3-carbamoyl-pyrazol-1-yl)acetate

To a solution of ethyl 2-(3-carbamoyl-4-nitro-pyrazol-1-yl)acetate (1 g,4.13 mmol) in MeOH (40 mL) was added Pd/C (0.3 g, 10% w/w) under N₂. Thesuspension was degassed under vacuum and purged with H₂ three times. Themixture was stirred under H₂ (15 Psi) at 20° C. for 12 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (780 mg, 89% yield) as white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 7.13 (s, 2H), 7.00 (s, 1H), 4.93 (s, 2H), 4.68 (s,2H), 4.14 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H).

Step 3—4-Amino-1-(2-hydroxyethyl)pyrazole-3-carboxamide

To a solution of ethyl 2-(4-amino-3-carbamoyl-pyrazol-1-yl)acetate (770mg, 3.59 mmol) in a mixed solvent of THF (120 mL) and MeOH (15 mL) wasadded LiBH₄ (156 mg, 7.18 mmol) at 0° C., and the mixture was stirred at0° C. for 1 hour. On completion, the reaction mixture was quenched withwater (0.5 mL), and then concentrated in vacuo to give a residue. Theresidue was diluted with water 20 mL, and then extracted with DCM (100mL×3). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (600 mg, 98% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.10 (s, 2H), 6.93 (s, 1H),4.97 (t, J=5.6 Hz, 1H), 4.61 (s, 2H), 4.01 (t, J=5.6 Hz, 2H), 3.69 (q,J=5.6 Hz, 2H).

Tert-ButylN-[4-[4-[[3-carbamoyl-1-(2-oxoethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cvclopropylmethyl)carbamate(Intermediate HG)

Step 1—Tert-butylN-[4-[4-[[3-carbamoyl-1-(2-hydroxyethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of 4-amino-1-(2-hydroxyethyl)pyrazole-3-carboxamide (500mg, 2.94 mmol, Intermediate HF) in DMF (15 mL) was added2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (844 mg, 2.35 mmol, synthesized via Steps 1-4 of Intermediate DF),DIPEA (1.14 g, 8.81 mmol) and HATU (1.23 g, 3.23 mmol). The mixture wasstirred at 25° C. for 0.5 hour. On completion, the reaction mixture wasdiluted with water 80 mL, filtered to give the filter cake which wasdried in vacuo to give the title compound (1.00 g, 67% yield) as lightyellow solid; LC-MS (ESI⁺) m/z 512.4 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-(2-oxoethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-(2-hydroxyethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(300 mg, 486 umol) in THF (50 mL) was added DMP (412 mg, 973 umol), andthe mixture was stirred at 10° C. for 16 hours. On completion, thereaction mixture was filtered to give the filtrate, which was thenconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (FA condition) to give the title compound (90.0 mg, 33% yield)as light yellow solid; LC-MS (ESI⁺) m/z 528.3 (M+H+H₂O)⁺.

1-[2-[2-[2-[3-(2-Aminoethoxy)propoxy]ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide(Intermediate HH)

Step1—2-[2-[2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylMethane Sulfonate

To a solution of tert-butylN-[2-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]ethyl]carbamate(4.00 g, 11.9 mmol, CAS #1404111-67-6) and TEA (3.00 g, 29.6 mmol) inDCM (40 mL) was added MsCl (1.77 g, 15.4 mmol) at 0° C. The reactionmixture was stirred at 25° C. for 2 hours. On completion, the mixturewas quenched with water (20 mL), and extracted with DCM. The organiclayer was washed with water (50 mL) and brine (50 mL), dried withNa₂SO₄, and filtered. The filtrate was concentrated in vacuo to give thetitle compound (4.65 g, 94% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 5.05 (s, 1H), 4.41-4.31 (m, 2H), 3.79-3.74 (m, 2H), 3.69-3.58(m, 12H), 3.56-3.51 (m, 2H), 3.34-3.27 (m, 2H), 3.08 (s, 3H), 1.44 (s,9H).

Step 2—Tert-ButylN-[2-[2-[2-[2-[2-(3-carbamoyl-4-nitro-pyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethoxylethyl]carbamate

To a solution of2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (4.59 g, 11.1 mmol) and4-nitro-1H-pyrazole-3-carboxamide (1.50 g, 9.61 mmol, Intermediate CJ)in DMF (25 mL) was added Cs₂CO₃ (7.20 g, 22.1 mmol). The reactionmixture was stirred at 125° C. for 15 hours. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo, and the residuewas purified by reverse phase (0.1% HCl condition) to give the titlecompound (1.45 g, 31% yield) as yellow oil. LC-MS (ESI⁺) m/z 498.3(M+Na)⁺.

Step3—1-[2-[2-[2-[3-(2-Aminoethoxy)propoxy]ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide

To a solution of tert-butylN-[2-[2-[2-[2-[2-(3-carbamoyl-4-nitro-pyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.45 g, 2.99 mmol) in DCM (6 mL) was addedHCl/dioxane (10 mL). The reaction mixture was stirred at 25° C. for 20minutes. On completion, the mixture was concentrated in vacuo to givethe title compound (1.19 g, 94% yield) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 8.83 (s, 1H), 8.02 (s, 1H), 7.77 (s, 1H), 4.40-4.30 (m, 2H),3.81 (t, J=5.2 Hz, 2H), 3.60 (t, J=5.2 Hz, 2H), 3.56-3.53 (m, 8H),3.49-3.46 (m, 4H), 2.98-2.91 (m, 2H); LC-MS (ESI⁺) m/z 376.2 (M+H)⁺.

4-Amino-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]pyrazole-3-carboxamide(Intermediate HI)

Step1—1-[2-[2-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide

To a solution of1-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide(0.50 g, 1.21 mmol, HCl, Intermediate HH) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (352 mg, 1.27mmol, Intermediate R) in dioxane (8 mL) was added DIPEA (785 mg, 6.07mmol). The reaction mixture was stirred at 115° C. for 12 hours. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by silica gel chromatography to give the title compound (280mg, 37% yield) as yellow oil. LC-MS (ESI⁺) m/z 632.3 (M+H)⁺.

Step2—4-Amino-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]pyrazole-3-carboxamide

To a solution of1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-4-nitro-pyrazole-3-carboxamide (140 mg, 222umol) in THF (5 mL) was added Pd/C (0.3 g, 20% wt). The reaction mixturewas stirred at 25° C. for 0.4 hour under H₂ (15 Psi). On completion, themixture was filtered and the filtrate was concentrated in vacuo to givethe title compound (100 mg, 75% yield) as yellow oil. LC-MS (ESI⁺) m/z602.1 (M+H)⁺.

2-[2-(Tert-butoxycarbonylamino)-4-pyridyl]oxazole-4-carboxylic Acid(Intermediate HJ)

Step 1—Ethyl2-[2-(tert-butoxycarbonylamino)-4-pyridyl]oxazole-4-carboxylate

A mixture of tert-butyl N-(4-bromo-2-pyridyl)carbamate (1.00 g, 3.66mmol, CAS #207799-10-8), ethyl oxazole-4-carboxylate (517 mg, 3.66 mmol,CAS #170487-38-4), tris-o-tolylphosphane (223 mg, 732 umol), Pd(OAc)₂(82.2 mg, 366 umol) and Cs₂CO₃ (2.39 g, 7.32 mmol) in DMF (10 mL) wasdegassed and purged with N₂ 3 times, and then the mixture was stirred at70° C. for 17 hrs under N₂ atmosphere. On completion, the mixture wasdiluted with water (300 mL), and extracted with EA (3×200 mL). Theorganic layer was washed with water (400 mL), dried over Na₂SO₄,filtrated and concentrated in vacuo to give the title compound (1.22 g,50% yield) as a yellow solid. LC-MS (ESI⁺) m/z 278.2 (M+H−56)⁺.

Step 2—2-[2-(Tert-butoxycarbonylamino)-4-pyridyl]oxazole-4-carboxylicAcid

To a solution of methyl2-[2-(tert-butoxycarbonylamino)-4-pyridyl]oxazole-4-carboxylate (1.17 g,3.66 mmol) in MeOH (5 mL) and H₂O (5 mL) was added LiOH·H₂O (439 mg,18.3 mmol). The mixture was stirred at 15° C. for 6 hours. Oncompletion, the mixture was concentrated, then 1M HCl was added to theresidue until the pH=5-6, and then filtered. The filter cake was driedin vacuo to give the title compound (400 mg, 28% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.37 (br s, 1H), 10.31-10.12 (m,1H), 9.13-8.95 (m, 1H), 8.52 (s, 1H), 8.50 (d, J=5.4 Hz, 1H), 7.63-7.58(m, 1H), 1.69-1.53 (m, 9H); LC-MS (ESI⁺) m/z 250.2 (M+H−56)⁺.

4-[2-[2-[(2S)-2-(aminomethyl)morpholin-4-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate HK)

Step 1—Tert-ButylN-[[(2S)-4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate

To a solution of2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethanesulfonate (460 mg, 1.05 mmol, synthesized via Steps 1-2 ofExample 184) and tert-butyl N-[[(2R)-morpholin-2-yl]methyl]carbamate(453 mg, 2.09 mmol, CAS #186202-57-3) in ACN (15 mL) was added KI (17.4mg, 105 umol) and NaHCO₃ (264 mg, 3.14 mmol). The reaction mixture wasstirred at 80° C. for 17 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (530 mg, 91% yield) as ayellow solid. LC-MS (ESI⁺) m/z 560.2 (M+H)⁺.

Step2—4-[2-[2-[(2S)-2-(aminomethyl)morpholin-4-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[[(2S)-4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate (630 mg, 1.13 mmol)in DCM (6 mL) was added HC/dioxane (10 mL). The reaction mixture wasstirred at 15° C. for 1 hr. On completion, the mixture was concentratedin vacuo to give the title compound (550 mg, 99% yield) as a yellowsolid. LC-MS (ESI⁺) m/z 460.4 (M+H)⁺.

Methyl 4-nitro-1H-pyrazole-3-carboxylate (Intermediate HL)

To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid (50.0 g, 318mmol, CAS #5334-40-7) in MeOH (250 mL) was added SOCl₂ (56.8 g, 477mmol). The mixture was stirred at 70° C. for 5 hrs. On completion, themixture was concentrated in vacuo to give the title compound (54.0 g,99% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 14.40 (s, 1H),9.98 (s, 1H), 3.89 (s, 3H).

Tert-Butyl(cvclopropylmethyl)(4-(4-((1-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate(Intermediate HM)

Step1—4-(4-(2-(2-((Tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoic(isopropylcarbonic)anhydride

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(trifluoromethyl)pyrazol-1-yl]benzoicacid (700 mg, 960 umol, Intermediate EG) in THF (10 mL) was added TEA(194 mg, 1.92 mmol). Then, the reaction mixture was cooled to −10° C.After, isopropyl carbonochloridate (235 mg, 1.92 mmol) was added and thereaction mixture was stirred at −10° C. for 2 hours. On completion, thereaction mixture was filtered. The filtrate was concentrated in vacuo togive the title compound (720 mg, 91% yield) as white solid. LC-MS (ESI⁺)m/z 699.0 (M+H)⁺.

Step 2—Tert-Butyl(cyclopropylmethyl)(4-(4-((1-(4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

To a solution of isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(trifluoromethyl)pyrazol-1-yl]benzoate(720 mg, 876 umol) in THF (20 mL) was added NaBH₄ (66.3 mg, 1.75 mmol)and water (63.1 mg, 3.50 mmol). The residue was mixture was stirred at0° C. for 1 hour. On completion, the reaction mixture was quenched withwater (5 mL) and the mixture was extracted with DCM (3×50 mL). Thecombined organic layer was washed with brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thetitle compound (520 mg, 99% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 9.06 (s, 1H), 8.88 (s, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.42 (s,1H), 8.36 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64 (d, J=4.8 Hz, 1H), 7.51(d, J=8.4 Hz, 2H), 4.78 (s, 2H), 3.96 (d, J=7.2 Hz, 2H), 1.59 (s, 9H),0.93-0.81 (m, 1H), 0.47-0.42 (m, 2H), 0.30-0.26 (m, 2H); LC-MS (ESI⁺)m/z 599.2 (M+H)⁺.

Step 3—Tert-Butyl(cyclopropylmethyl)(4-(4-((1-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-Vl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

To a solutionoftert-butylN-(cyclopropylmethyl)-N-[4-[4-[[1-[4-(hydroxymethyl)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(320 mg, 535 umol) in DCM (10 mL) was added DMP (454 mg, 1.07 mmol). Thereaction mixture was stirred at 25° C. for 5 hours. On completion, thereaction mixture was quenched with saturated Na₂S₂O₃ (20 mL), andextracted with DCM (3×30 mL). The combined organic layers was washedwith saturated NaHCO₃ (2×20 mL), then washed with brine (30 mL), driedover with anhydrous sodium sulfate, filtered and concentrated in vacuo.The residue was purified by prep-HPLC (0.1% HCl) to give the titlecompound (123 mg, 39% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ10.08 (s, 1H), 9.08 (s, 1H), 9.01 (d, J=5.2 Hz, 1H), 8.98 (s, 1H), 8.57(s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.8 Hz, 2H), 7.45 (s, 1H),7.39 (s, 1H), 3.35 (s, 2H), 1.67 (s, 9H), 1.15-1.05 (m, 1H), 0.78-0.76(m, 2H), 0.45-0.44 (m, 2H).

3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione(3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione)

Step 1 —[1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate

To a solution of 3-hydroxy-1-[(4-methoxyphenyl) methyl]piperidine-2,6-dione (43.0 g, 173 mmol, Intermediate IQ) and pyridine(27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethylsulfonyltrifluoromethanesulfonate (73.0 g, 258.74 mmol) dropwise at 0° C. Themixture was stirred at 0-10° C. for 1.5 hours under N₂. On completion,the mixture was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give the title compound (45.0 g,68% yield) as light yellow gum. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=8.4Hz, 2H), 6.85-6.82 (m, 2H), 5.32-5.28 (m, 1H), 4.91 (s, 2H), 3.79 (s,3H), 3.02-2.97 (m, 1H), 2.79-2.74 (m, 1H), 2.41-2.35 (m, 2H).

Step2—3-(5-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.90 g, 21.6mmol, Intermediate IP) in THF (300 mL) was added t-BuOK (3.63 g, 32.3mmol) at 0° C. The mixture was stirred at 0-10° C. for 1 hour under N₂.Then a solution of [1-[(4-methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (9.87 g, 25.9 mmol) in THF(100 mL) was added to the reaction mixture at 0-10° C. during 30minutes. The mixture was stirred at 0-10° C. for 30 minutes under N₂. Anadditional solution of [1-[(4-methoxyphenyl) methyl]-2,6-dioxo-3-piperidyl] trifluoromethanesulfonate (2.47 g, 6.47 mmol) inTHF (20 mL) was added to the reaction mixture at 0-10° C. dropwise. Themixture was then stirred at 0-10° C. for another 30 minutes under N₂. Oncompletion, the reaction was quenched water (400 mL) and extracted withEA (3×200 mL). The combined organic layer was concentrated in vacuo. Theresidue was triturated with EA (80 mL) and filtered. The filter cake wascollected and dried in vacuo to give the title compound (6.70 g, 67%yield) as light yellow solid. The filtrate was also concentrated invacuo and the residue was purified by column chromatography to giveanother batch title compound (1.80 g, 18% yield) as light yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (d, J=1.6 Hz, 1H), 7.21-7.16 (m, 3H),7.01 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 5.55-5.51 (m, 1H),4.84-4.73 (m, 2H), 3.72 (s, 3H), 3.33 (s, 3H), 3.04-3.00 (m, 1H),2.83-2.67 (m, 2H), 2.07-2.05 (m, 1H).

Step 3—3-(5-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione

To a mixture of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (8.50 g, 18.6 mmol) in toluene (50 mL) was addedmethanesulfonic acid (33.8 g, 351 mmol, 25 mL) at room temperature (15°C.). The mixture was stirred at 120° C. for 2 hours. On completion, thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was poured into ice/water (200 mL), and extractedwith EA (3×100 mL). The combined organic layer was washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas triturated with EA (80 mL) and filtered. The filtrate cake wascollected and dried in vacuo to give the title compound (4.20 g, 67%yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H),7.47 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H),5.40-5.35 (m, 1H), 2.34 (s, 3H), 2.92-2.88 (m, 1H), 2.71-2.60 (m, 2H),2.03-1.99 (m, 1H).

3-[5-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate HO)

Step 1—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (350mg, 1.04 mmol, Intermediate HN) and tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (629 mg, 2.59 mmol,synthesized via Step 1 of Intermediate CQ) in DMF (10 mL) was added TEA(2.62 g, 25.8 mmol, 3.60 mL), CuI (98.5 mg, 517 umol) and Pd(PPh₃)₂Cl₂(363 mg, 517 umol). The reaction mixture was stirred at 80° C. for 1.5hours under N₂. On completion, the mixture was filtered, and thefiltrate was concentrated in vacuo to give a residue. The residue wasdissolved in DCM (20 mL) and thiourea (resin) (300 mg) was added. Themixture was stirred at 20° C. for 12 hours. Then the reaction mixturewas filtered and the filtrate was concentrated in vacuo to give aresidue. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (208 mg, 40% yield) as yellow solid. LC-MS(ESI⁺) m/z 523.3 (M+Na)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H),7.34 (d, J=0.8 Hz, 1H), 7.22-7.12 (m, 2H), 6.83-6.70 (m, 1H), 5.40 (dd,J=5.6, 12.8 Hz, 1H), 4.40 (s, 2H), 3.67-3.61 (m, 2H), 3.60-3.54 (m, 2H),3.40 (t, J=6.0 Hz, 2H), 3.35 (s, 3H), 3.08 (q, J=6.0 Hz, 2H), 2.96-2.84(m, 1H), 2.73-2.60 (m, 2H), 2.09-2.00 (m, 1H), 1.38 (s, 9H).

Step 2—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate (100 mg, 199 umol) in THF (10 mL)was added Pd(OH)₂/C (50 mg, 10 wt %) and Pd/C (50 mg, 10 wt %), and thereaction mixture was stirred under H₂ (15 psi) for 1 hr. On completion,the residue was filtered and the filtrate was concentrated in vacuo togive the title compound (100 mg, 99.2% yield) as yellow oil. LC-MS(ESI⁺) m/z 527.4 (M+Na)⁺.

Step3—3-[5-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethyl]carbamate (100 mg, 198.19 umol) in DCM (2 mL) wasadded HCl/dioxane (4 M, 2 mL), and the reaction mixture was stirred at20° C. for 1 hr. On completion, the mixture was concentrated in vacuo togive the title compound (85.0 mg, 97% yield) as yellow oil. LC-MS (ESI⁺)m/z 405.2 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.09-6.96 (m, 2H), 6.88(d, J=7.6 Hz, 1H), 5.34 (dd, J=5.2, 12.8 Hz, 1H), 3.57-3.49 (m, 6H),3.41 (t, J=6.4 Hz, 2H), 3.33 (s, 3H), 2.98-2.83 (m, 2H), 2.76-2.68 (m,1H), 2.64-2.68 (m, 2H), 2.63-2.54 (m, 1H), 2.46-2.44 (m, 1H), 2.04-1.97(m, 1H), 1.87-1.78 (m, 2H).

3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(Intermediate HP)

Step 1—2-Bromo-N-methyl-6-nitro-aniline

To a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0 g, 181 mmol, CAS#58534-94-4) in THF (40 mL) was added MeNH₂ (2 M, 400 mL). The reactionmixture was stirred at 60° C. for 12 hours. On completion, the reactionmixture was poured into sat.NaHCO₃ (30 mL) and extracted with EA (3×200mL). The combined organic layers were washed with brine (2×200 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (40.0 g, 95% yield) as red oil. LC-MS (ESI⁺) m/z230.9 (M+H)⁺.

Step 2—3-Bromo-N2-methyl-benzene-1,2-diamine

To a mixture of 2-bromo-N-methyl-6-nitro-aniline (23.0 g, 99.5 mmol) inEA (300 mL) and H₂O (10 mL) was added AcOH (100 mL). The mixture waswarmed to 50° C. Then Fe (22.2 g, 398 mmol) was added to the reactionmixture and the mixture was heated to 80° C. about 4 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was diluted with water (100 mL) and extracted with EA (3×200mL). The combined organic layers was dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (20.0 g, 99% yield) asred oil. ¹H NMR (400 MHz, DMSO-d₆) δ 6.73-6.70 (m, 1H), 6.68-6.60 (m,2H), 5.02 (s, 2H), 3.67 (s, 1H), 2.58 (s, 3H).

Step 3—4-Bromo-3-methyl-1H-benzimidazol-2-one

To a mixture of 3-bromo-N2-methyl-benzene-1,2-diamine (20.0 g, 99.4mmol) in ACN (300 mL) was added CDI (32.2 g, 198 mmol). The reactionmixture was stirred at 85° C. for 12 hours under N₂ atmosphere. Oncompletion, the reaction mixture was concentrated in vacuo. The reactionmixture was diluted with water (200 mL), where a solid precipitate wasformed, which was filtered off. The solid was washed with water (1 L)and dried in vacuo to give the title compound (20.0 g, 88% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H), 7.14 (dd, J=1.2,8.0 Hz, 1H), 7.00-6.95 (m, 1H), 6.93-6.87 (m, 1H), 3.55 (s, 3H).

Step4—3-(4-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (12.0 g, 52.8mmol) in THF (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reactionmixture was stirred at 0° C. for 0.5 hr. Subsequently,[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (20.1 g, 52.8 mmol, Intermediate IQ) in asolution of THF (100 mL) was added dropwise. The resulting reactionmixture was stirred at 20° C. for 0.5 hr under N₂. On completion, thereaction mixture was quenched with saturated NH₄Cl (100 mL), andextracted with ethyl acetate (200 mL). The combined organic layers werewashed with brine (2×100 mL), dried over anhydrous sodium sulfate,filtered, the filtrate was concentrated in vacuo. The crude product waspurified by reversed-phase HPLC (0.1% FA condition) to give the titlecompound (13.3 g, 55% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 7.38 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.0 Hz, 1H), 6.84 (d, J=8.8 Hz,2H), 6.80 (t, J=8.0 Hz, 1H), 6.48-6.40 (d, J=8.0 Hz, 1H), 5.22 (dd,J=5.2, 12.8 Hz, 1H), 5.04-4.93 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H),3.12-2.98 (m, 1H), 2.93-2.77 (m, 1H), 2.62 (dq, J=4.4, 13.2 Hz, 1H),2.20-2.17 (m, 1H).

Step5—3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione(13.3 g, 29.0 mmol) in a mixed solvent of Tol. (80 mL) and methanesulfonic acid (40 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 120° C. for 2 hrs under N₂ atmosphere.On completion, the reaction mixture was concentrated in vacuo to removetoluene. The residue was added 200 mL of ice water, and then white solidprecipitate formed. The mixture was filtered and the filtered cake wascollected and dried over in vacuo to give the title compound (7.30 g,74% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H),7.25 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.05-6.93 (m, 1H), 5.41(dd, J=5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 2.96-2.83 (m, 1H), 2.78-2.59 (m,2H), 2.08-2.00 (m, 1H).

3-[4-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate HO)

Step 1—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate

To a mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (100mg, 295 umol, Intermediate HP) and tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (93.5 mg, 384 umol,synthesized via Step 1 of Intermediate CQ) in DMF (5 mL) was added CuI(5.63 mg, 29.5 umol), Pd(PPh₃)₂Cl₂ (20.7 mg, 29.5 umol) and TEA (538 mg,5.32 mmol, 740 uL). The reaction mixture was heated at 80° C. for 30minutes under microwave. On completion, the reaction mixture wasconcentrated in vacuo. The residue was purified by prep-HPLC (column:Kromasil 150*25 mm*10 um; mobile phase: [water (0.225% FA)-ACN]) to givethe title compound (55.0 mg, 34% yield, FA) as brown solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.18 (d, J=7.6 Hz, 1H), 7.13 (d, J=7.6Hz, 1H), 7.08-7.00 (m, H), 6.76 (s, 1H), 5.41 (dd, J=4.4, 12.4 Hz, 1H),4.47 (s, 2H), 3.69-3.65 (m, 2H), 3.65 (s, 3H), 3.57 (d, J=4.4 Hz, 2H),3.40 (t, J=6.0 Hz, 2H), 3.08 (d, J=5.6 Hz, 2H), 2.96-2.84 (m, 1H),2.77-2.63 (m, 2H), 2.09-1.97 (m, 1H), 1.37 (s, 9H). LC-MS (ESI⁺) m/z501.4 (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate (50.0 mg, 99.8 umol) in THF (4 mL)was added Pd/C (15 mg, 10 wt %) and Pd(OH)₂/C (15 mg, 10 wt %). Thereaction mixture was stirred at 25° C. for 1 hour under H₂ (15 Psi)atmosphere. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound (50.0 mg, 99% yield) asbrown oil. LC-MS (ESI⁺) m/z 505.4 (M+H)⁺.

Step3—3-[4-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]carbamate (50.0 mg, 99.0 umol) in DCM (5 mL) wasadded HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25°C. for 1 hour. On completion, the reaction mixture was concentrated invacuo to give the title compound (43.0 mg, 98% yield, HCl) as colourlessoil. LC-MS (ESI⁺) m/z 405.3 (M+H)⁺.

4-[2-[2-[(2R)-2-(aminomethyl)morpholin-4-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate HR)

Step 1—Tert-ButylN-[[(2R)-4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate

To a solution of2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethanesulfonate (500 mg, 1.14 mmol, synthesized via Steps 1-2 ofExample 184), tert-butyl N-[[(2S)-morpholin-2-yl]methyl] carbamate (492mg, 2.28 mmol, CAS #875551-59-0) in ACN (20.0 mL) was added KI (18.8 mg,113 umol) and NaHCO₃ (286 mg, 3.41 mmol). The mixture was stirred at 80°C. for 16 hrs. On completion, the mixture was concentrated in vacuo. Themixture was purified by silica gel column (DCM:MeOH=50:1) to give thetitle compound (400 mg, 62% yield) as yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.38-8.13 (m, 1H), 7.46-7.40 (m, 1H), 7.04 (d, J=7.2 Hz, 1H),6.83 (d, J=8.8 Hz, 1H), 6.43 (s, 1H), 4.94-4.81 (m, 2H), 3.80-3.72 (m,1H), 3.67-3.54 (m, 6H), 3.41-3.34 (m, 2H), 3.34-3.18 (m, 1H), 3.07-2.94(m, 1H), 2.84-2.75 (m, 2H), 2.73-2.66 (m, 2H), 2.61-2.49 (m, 2H),2.21-2.09 (m, 1H), 2.08-2.01 (m, 1H), 1.95-1.85 (m, 1H), 1.69-1.55 (m,1H), 1.36 (s, 9H).

Step2—4-[2-[2-[(2R)-2-(aminomethyl)morpholin-4-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[[(2R)-4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate (380 mg, 679 umol) inDCM (3.00 mL) was added HCV/dioxane (4 M, 5.00 mL). The mixture wasstirred at 15° C. for 1 hr. On completion, the mixture was concentratedin vacuo to give the title compound (330 mg, 95% yield) as yellow solid.LC-MS (ESI⁺) m/z 460.1 (M+H)⁺.

3-(Difluoromethyl)-4-nitro-1H-pyrazole (Intermediate HS)

Step 1—1-Benzyl-1H-pyrazole-3-carbaldehyde

To a solution of 1H-pyrazole-3-carbaldehyde (5.00 g, 52.0 mmol, CAS #:3920-50-1) and BnBr (9.34 g, 54.6 mmol) in DMF (50 mL) was added Cs₂CO₃(42.4 g, 130 mmol). The reaction mixture was stirred at 25° C. for 1hour. On completion, the reaction mixture was diluted with water,extracted with ethyl acetate (3×100 mL). The combined organic layers waswashed with brine (50 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. The crude product was purified by silica gelchromatography (Petroleum ether:Ethyl acetate=20:1) to give the titlecompound (8.00 g, 83% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 10.02 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.43-7.33 (m, 3H), 7.29-7.24(m, 2H), 6.85 (d, J=2.4 Hz, 1H), 5.42 (s, 2H).

Step 2—1-Benzyl-3-(difluoromethyl)-1H-pyrazole

To a solution of 1-benzylpyrazole-3-carbaldehyde (5.00 g, 26.9 mmol) inDCM (30 mL) was added DAST (17.3 g, 107 mmol) at 0° C. The reactionmixture was stirred at 25° C. for 5 hours. On completion, the reactionmixture was quenched with methanol (30 mL) at 0° C. After, the mixturewas concentrated in vacuo. The crude product was purified by silica gelchromatography (petroleum ether:ethyl acetate=20:1) to give the titlecompound (3.30 g, 59% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ7.43-7.36 (m, 3H), 7.27-7.21 (m, 2H), 6.91-6.57 (m, 1H), 6.55-6.51 (m,1H), 5.35 (s, 2H); LC-MS (ESI⁺) m/z 209.1 (M+H)⁺.

Step 3—3-(Difluoromethyl)-1H-pyrazole

To a solution of 1-benzyl-3-(difluoromethyl)pyrazole (1.00 g, 4.80 mmol)in methanol (20 mL) was added Pd(OH)₂/C (0.1 g, 10% purity) under N₂atmosphere. The suspension was degassed and purged with H₂ for 3 times.The mixture was stirred at 40° C. for 12 hrs under H₂ (50 Psi). Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (470 mg, 83% yield) as colorless oil. ¹H NMR(400 MHz, DMSO-d₆) δ 13.16 (s, 1H), 7.85 (s, 1H), 7.14-6.82 (m, 1H),6.52 (s, 1H).

Step 4—3-(Difluoromethyl)-4-nitro-1H-pyrazole

To a solution of 3-(difluoromethyl)-1H-pyrazole (470 mg, 3.98 mmol) inH₂SO₄ (5 mL) was carefully added a 65% solution of HNO₃ (965 mg, 9.95mmol) dropwise at 0° C. After stirring for 10 minutes, the reactionmixture was heated to 115° C., and stirred for 12 hrs. On completion,the reaction mixture was cooled to 25° C. Then, the reaction mixture waspoured onto the (100 mL) ice, extracted with ethyl acetate (3×50 mL).The combined organic layers was washed with brine (2×50 mL), dried overwith anhydrous sodium sulfate, filtered and concentrated in vacuo togive the title compound (530 mg, 82% yield). ¹H NMR (400 MHz, DMSO-d₆) δ14.41 (s, 1H), 9.04 (s, 1H), 7.50-7.17 (m, 1H), 7.50-7.17 (m, 1H).

14-(3-(Difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-3,6,9,12-tetraoxatetradecan-1-amine(Intermediate HT)

Step 1—Tert-ButylN-[2-[2-[2-[2-[2-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of 3-(difluoromethyl)-4-nitro-1H-pyrazole (200 mg, 1.23mmol, Intermediate HS) and2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (560 mg, 1.35 mmol, synthesized via Step 1 ofIntermediate HH) in DMF (5 mL) was added Cs₂CO₃ (799 mg, 2.45 mmol). Thereaction mixture was stirred at 130° C. for 12 hrs. On completion, thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by prep-HPLC (condition: 0.1% HCl) togive the title compound (220 mg, 36% yield) as a yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ 8.99 (s, 1H), 7.51-7.16 (m, 11H), 6.76 (s, 1H), 4.41 (t,J=5.2 Hz, 2H), 3.83 (t, J=5.2 Hz, 2H), 3.61-3.44 (m, 13H), 3.61-3.44 (m,1H), 3.05 (q, J=5.6 Hz, 2H), 1.37 (s, 8H); LC-MS (ESI⁺) m/z 505.4(M+Na)⁺.

Step2—14-(3-(Difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-3,6,9,12-tetraoxatetradecan-1-amine

To a solution of tert-butylN-[2-[2-[2-[2-[2-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (220 mg, 456 umol) in DCM (5 mL) was addedHCl/dioxane (4 M, 114 uL). The reaction mixture was stirred at 20° C.for 15 min. On completion, the reaction mixture was concentrated invacuo to give the title compound (191 mg, 100% yield) as yellow oil.LC-MS (ESI⁺) m/z 383.0 (M+H)⁺.

4-((14-(4-Amino-3-(difluoromethyl)-1H-pyrazol-1-yl)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione(Intermediate HU)

Step1—4-((14-(3-(Difluoromethyl)-4-nitro-1H-pyrazol-1-yl)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of2-[2-[2-[2-[2-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethanamine (191 mg, 456 umol, Intermediate HT) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (139 mg, 502umol, Intermediate R) in dioxane (10 mL) was added DIPEA (295 mg, 2.28mmol). The reaction mixture was stirred at 115° C. for 12 hours. Oncompletion, the mixture was concentrated in vacuo. The crude product waspurified by prep-HPLC (condition: 0.10% HCl) to give the title compound(170 mg, 58% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10(s, 1H), 8.98 (s, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.45-7.18 (m, 1H), 7.14(d, J=8.4 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 6.60 (s, 1H), 5.06 (dd,J=4.8, 13.2 Hz, 1H), 4.43-4.37 (m, 2H), 3.82 (t, J=4.8 Hz, 2H),3.64-3.59 (m, 1H), 3.61 (d, J=4.8 Hz, 1H), 3.56-3.46 (m, 14H), 2.97-2.80(m, 1H), 2.65-2.55 (m, 2H), 2.09-1.98 (m, 1H); LC-MS (ESI⁺) m/z 639.1(M+H)⁺.

Step2—4-((14-(4-Amino-3-(difluoromethyl)-1H-pyrazol-1-yl)-3,6,9,12-tetraoxatetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of4-[2-[2-[2-[2-[2-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (170mg, 266 umol) in methanol (20 mL) was added Pd/C (0.05 g, 10% wt) underN₂ atmosphere. The suspension was degassed and purged with H₂ for 3times. The mixture was stirred at 20° C. for 0.5 hr under H₂ (15 Psi).On completion, the reaction mixture was filtered and concentrated invacuo to give the title compound (130 mg, 80% yield) as yellow oil.LC-MS (ESI⁺) m/z 609.1 (M+H)⁺.

4-Fluoro-2-(2-oxo-3-piperidyl)isoindoline-1,3-dione (Intermediate HV

To a solution of 4-fluoroisobenzofuran-1,3-dione (661 mg, 3.98 mmol, CAS#652-39-1), KOAc (1.21 g, 12.3 mmol) in HOAc (30 mL) was added3-aminopiperidin-2-one (0.50 g, 4.38 mmol CAS #1892-22-4). Then themixture was stirred at 90° C. for 16 hours. On completion, the mixturewas concentrated in vacuo to give a residue, which was then diluted withwater 60 mL, and filtered to give the filter cake (0.60 g, 57% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.97-7.86 (m, 2H), 7.79-7.66(m, 2H), 4.60 (dd, J=6.4, 12.0 Hz, 1H), 3.26-3.14 (m, 2H), 2.27-2.13 (m,1H), 2.06-1.96 (m, 1H), 1.95-1.86 (m, 2H).

4-(2-Aminoethylamino)-2-(2-oxo-3-piperidyl)isoindoline-1,3-dione(Intermediate HW)

Step 1—Tert-ButylN-[2-[[1,3-dioxo-2-(2-oxo-3-piperidyl)isoindolin-4-yl]amino]ethyl]carbamate

To a solution of tert-butyl N-(2-aminoethyl)carbamate (366 mg, 2.29mmol) in dioxane (20 mL) was added4-fluoro-2-(2-oxo-3-piperidyl)isoindoline-1,3-dione (0.6 g, 2.29 mmol,Intermediate HV) and DIPEA (1.48 g, 11.4 mmol), and the mixture wasstirred at 115° C. for 16 hours. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography to give the title compound (360 mg, 39.06% yield)as light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.81 (s, 1H), 7.55 (t,J=8.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.07-6.95 (m, 2H), 6.68 (t, J=5.6Hz, 1H), 4.50 (dd, J=6.0, 12.6 Hz, 1H), 3.44-3.34 (m, 2H), 3.24-3.16 (m,2H), 3.14-3.09 (m, 2H), 2.25-2.14 (m, 2H), 1.98-1.81 (m, 3H), 1.37 (s,9H).

Step 2—4-(2-Aminoethylamino)-2-(2-oxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[[1,3-dioxo-2-(2-oxo-3-piperidyl)isoindolin-4-yl]amino]ethyl]carbamate (350 mg, 869 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 3mL). The mixture was stirred at 5° C. for 0.5 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(280 mg, 91% yield) as yellow solid; LC-MS (ESI⁺) m/z 303.2 (M+H)⁺.

2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (IntermediateHX)

To a mixture of 3-aminopiperidine-2,6-dione (10.8 g, 65.8 mmol, HCl) andKOAc (18.2 g, 185 mmol) in HOAc (160 mL) was added5-fluoroisobenzofuran-1,3-dione (9.95 g, 59.9 mmol, CAS #319-03-9). Thenthe mixture was stirred at 90° C. for 16 hours. On completion, thereaction mixture was cooled to 25° C. and diluted with water (600 mL),and then stirred at 0° C. for 0.5 hour then filtered. The filter cakewas dried in vacuo to give the title compound (14.0 g, 84% yield) asblack brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 8.01 (dd,J=4.4, 8.0 Hz, 1H), 7.84 (dd, J=2.4, 7.6 Hz, 1H), 7.76-7.67 (m, 1H),5.17 (dd, J=5.6, 12.8 Hz, 1H), 2.97-2.83 (m, 1H), 2.65-2.51 (m, 2H),2.13-2.03 (m, 1H).

Tert-Butyl N-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (Intermediate HY)

To a solution of DMSO (1.57 g, 20.0 mmol) in DCM (20 mL) was added asolution of (COCl)₂ (2.04 g, 16.0 mmol) in DCM (15 mL) dropwise at −70°C. The mixture was stirred at this temperature for 10 minutes. Then asolution of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate(2 g, 8.02 mmol, CAS #139115-92-7) in DCM (15 mL) was added into theabove mixture slowly. After stirred at −70° C. for 50 minutes, TEA (6.49g, 64.2 mmol) was added and the reaction mixture was stirred at −70° C.for 0.5 hr. On completion, the mixture was quenched with water (30 mL)and separated. The aqueous phase was extracted with DCM (2×30 mL). Thenthe organic phase was combined and washed with brine (2×50 mL), driedover Na₂SO₄, and concentrated in vacuo to give the title compound (1.36g, 69% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H),6.80-6.74 (m, 1H), 4.18 (s, 2H), 3.63-3.53 (m, 4H), 3.39-3.34 (m, 2H),3.08-3.04 (m, 2H), 1.37 (s, 9H).

5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate HZ)

Step 1—Tert-Butyl4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]piperidine-1-carboxylate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (600 mg, 2.17mmol, Intermediate HX) and tert-butyl 4-aminopiperidine-1-carboxylate(522 mg, 2.61 mmol, CAS #502482-34-0) in DMSO (7 mL) was added DIPEA(1.40 g, 10.8 mmol, 1.89 mL). The reaction mixture was stirred at 130°C. for 1.5 hours. On completion, the mixture was diluted with H₂O (10mL), then filtered and the filtrate was concentrated in vacuo to givethe title compound (250 mg, 25% yield) as a yellow solid. LC-MS (ESI⁺)m/z 479.2 (M+Na)⁺.

Step2—2-(2,6-Dioxo-3-piperidyl)-5-(4-piperidylamino)isoindoline-1,3-dione

To a solution of tert-butyl4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]piperidine-1-carboxylate(350 mg, 766 umol) in DCM (4 mL) was added HC/dixoane (4 M, 4 mL). Thereaction mixture was stirred at 25° C. for 1 hour. On completion, themixture was concentrated in vacuo to give the title compound (300 m g,99% yield) as a yellow solid. LC-MS (ESI⁺) m/z 357.3 (M+H)⁺.

Step 3—Tert-ButylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(4-piperidylamino)isoindoline-1,3-dione (200mg, 509 umol, HCl) in THF (20 mL) was added TEA (103 mg, 1.02 mmol, 141uL), the mixture was stirred at 20° C. for 10 mins, then tert-butylN-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (163 mg, 661 umol,Intermediate HY), HOAc (91.7 mg, 1.53 mmol, 87.3 uL) and NaBH(OAc)₃ (215mg, 1.02 mmol) was added to the mixture, and the reaction mixture wasstirred at 20° C. for 16 hr. On completion, the mixture was filtered,and the filtrate was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (110 mg, 37% yield) as a yellow solid. LC-MS (ESI⁺) m/z588.1 (M+H)⁺.

Step4—5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethyl]carbamate(110 mg, 187 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL). Thereaction mixture was stirred at 25° C. for 1 hour. On completion, themixture was concentrated in vacuo to give the title compound (95.0 mg,97% yield) as a yellow solid. LC-MS (ESI⁺) m/z 488.3 (M+H)⁺.

4-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate IA)

Step 1—Tert-Butyl4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazine-1-carboxylate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (500 mg, 1.81mmol, Intermediate R), and tert-butyl piperazine-1-carboxylate (404 mg,2.17 mmol, CAS #143238-38-4) in dioxane (5.00 mL) was added DIPEA (1.17g, 9.05 mmol). The mixture was stirred at 115° C. for 16 hrs. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% HCl) to give the titlecompound (270 mg, 33% yield) as yellow solid. LC-MS (ESI⁺) m/z 465.2(M+Na)⁺.

Step 2—2-(2,6-Dioxo-3-piperidyl)-4-piperazin-1-yl-isoindoline-1,3-dione

To a solution of tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazine-1-carboxylate(270 mg, 610 umol) in DCM (2.00 mL) was added HCl/dioxane (4.00 M, 3.00mL). The mixture was stirred at 15° C. for 0.5 hour. On completion, themixture was concentrated in vacuo to give the title compound (230 mg,95% yield, HCl) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s,1H), 9.22 (s, 1H), 7.80-7.74 (m, 1H), 7.49-7.39 (m, 2H), 5.16-5.08 (m,1H), 3.53-3.48 (m, 4H), 3.33-3.19 (m, 4H), 2.95-2.83 (m, 1H), 2.70-2.61(m, 1H), 2.59-2.53 (m, 1H), 2.10-1.97 (m, 1H).

Step 3—Tert-ButylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-piperazin-1-yl-isoindoline-1,3-dione (100mg, 263 umol, HCl),2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate(86.4 mg, 263 umol, synthesized via Step 1 of Intermediate AM) in ACN(5.00 mL) was added KI (4.38 mg, 26.4 umol) and NaHCO₃ (66.5 mg, 791umol). The mixture was stirred at 80° C. for 16 hours. On completion,the mixture was concentrated in vacuo to give the title compound (100mg, 60% yield) as yellow solid, LC-MS (ESI⁺) m/z 574.4 (M+H)⁺.

Step4—4-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate (70.0 mg, 122 umol) in DCM(2.00 mL) was added HCl/dioxane (4.00 M, 4.00 mL). The mixture wasstirred at 15° C. for 0.5 hour. On completion, the mixture wasconcentrated in vacuo to give the title compound (60.0 mg, 80% yield,HCl) as yellow solid. LC-MS (ESI⁺) m/z 474.3 (M+H)⁺.

5-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate IB)

Step 1—Tert-Butyl4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate

5-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.5 g, 1.48mmol, Intermediate GA), tert-butyl piperazine-1-carboxylate (552 mg,2.97 mmol), Cs₂CO₃ (966 mg, 2.97 mmol) and[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]-phosphane(115 mg, 148 umol, CAS #1375325-68-0) in dioxane (10 mL) was degassedand then heated to 80° C. for 15 hours under N₂. On completion, themixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the titlecompound (100 mg, 14% yield) as a yellow solid. LC-MS (ESI⁺) m/z 465.1(M+Na)⁺.

Step 2—2-(2,6-Dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione

To a solution of tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazine-1-carboxylate(70 mg, 142 umol) in DCM (1 mL) was added HCl/dioxane (2 mL). Thereaction mixture was stirred at 20° C. for 1 hr. On completion, themixture was concentrated in vacuo to give the title compound (53.0 mg,98% yield, HCl) as a yellow solid. LC-MS (ESI⁺) m/z 343.1 (M+H)⁺.

Step 3—Tert-ButylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (53 mg,140 umol, HCl) and tert-butylN-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (45 mg, 182 umol,Intermediate HY) in THF (10 mL) was added KOAc (27.5 mg, 280 umol). Onehour later, NaBH(OAc)₃ (59.3 mg, 280 umol) was added and the reactionmixture was stirred at 20° C. for 14 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography (SiO₂) to give the title compound (70 mg, 87% yield) asyellow oil. LC-MS (ESI⁺) m/z 574.3 (M+H)⁺.

Step4—5-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate (90.0 mg, 157 umol) in DCM(2 mL) was added HCl/dioxane (4 mL). The reaction mixture was stirred at20° C. for 3 hrs. On completion, the mixture was concentrated in vacuoto give the title compound (80 mg, 100% yield, HCl) as a yellow solid.LC-MS (ESI⁺) m/z 474.2 (M+H)⁺.

5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]azetidin-3-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate IC)

Step 1—Tert-Butyl3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]azetidine-1-carboxylate

A mixture of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (500mg, 1.48 mmol, Intermediate GA), tert-butyl3-aminoazetidine-1-carboxylate (383 mg, 2.22 mmol, CAS #193269-78-2),Brettphos-G3 (134 mg, 148 umol), and Cs₂CO₃ (1.45 g, 4.45 mmol) indioxane (50 mL) was degassed and purged with N₂ 3 times. Then themixture was stirred at 90° C. for 2 hours under N₂ atmosphere. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by pre-HPLC to give the title compound (90.0 mg, 13% yield) asyellow solid. LC-MS (ESI⁺) m/z 451.1 (M+Na)⁺.

Step2—5-(Azetidin-3-ylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butyl3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]azetidine-1-carboxylate(100 mg, 233 umol) in THF (5 mL) was added HCl/dioxane (4 M, 5 mL). Themixture was stirred at 20° C. for 2 hours. On completion, the mixturewas concentrated in vacuo to give the title compound (85.0 mg, 99%yield) as yellow solid. LC-MS (ESI⁺) m/z 329.0 (M+H)⁺.

Step 3—Tert-ButylN-[2-[2-[2-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]azetidin-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a mixture of5-(azetidin-3-ylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(85.0 mg, 233 umol), tert-butylN-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (57.6 mg, 233 umol,Intermediate HY) in THF (10 mL) and DMF (10 mL) was added TEA (23.5 mg,233 umol, 32.4 uL). The reaction mixture was stirred for 0.5 hour. ThenHOAc (13.9 mg, 233 umol) and NaBH(OAc)₃ (98.7 mg, 466 umol) was added tothe reaction mixture, and the mixture was stirred at 20° C. for 48 hoursunder N₂ atmosphere. On completion, the mixture was concentrated invacuo. The residue was purified by prep-HPLC to give the title compound(60.0 mg, 40% yield) as yellow oil. LC-MS (ESI⁺) m/z 560.4 (M+H)⁺.

Step4—5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]azetidin-3-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]azetidin-1-yl]ethoxy]ethoxy]ethyl]carbamate (60.0 mg, 107 umol) in THF(5 mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at 25°C. for 2 hrs. On completion, the mixture was concentrated in vacuo togive the title compound (50.0 mg, 95% yield) as yellow solid. LC-MS(ESI⁺) m/z 460.3 (M+H)⁺.

Tert-Butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (IntermediateID)

To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethylmethanesulfonate (2.30 g, 7.03 mmol, synthesized via Step 1 ofIntermediate AM) in DMF (20 mL) was added NaN₃ (913 mg, 14.1 mmol). Thereaction mixture was stirred at 80° C. for 12 hrs. On completion, themixture was diluted with water (50 mL), and extracted with DCM (2×30mL). The organic layer was washed with brine (50 mL), dried under N₂ togive the title compound (1.60 g, 83% yield) as yellow oil. LC-MS (ESI⁺)m/z 297.1 (M+Na)⁺.

4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate IE)

Step 1—Tert-ButylN-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (348 mg, 1.27 mmol,Intermediate ID), CuSO₄ (507 ug, 3.18 umol) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (1.26mg, 6.36 umol) in a mixed solvent of H₂O (2 mL) and t-BuOH (2 mL) wasadded2-(2,6-dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1,3-dione (200mg, 636 umol, Intermediate DN). The reaction mixture was stirred at 60°C. for 2 hours. On completion, the reaction mixture was diluted withwater (10 mL) and extracted with EA (20 mL×3). The combined organiclayers dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatography(PE/EA=1/1) to give the title compound (0.30 g, 78% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.99 (s, 1H), 7.57 (t,J=7.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.12-7.02 (m, 2H), 6.76 (t, J=5.2Hz, 1H), 5.06 (dd, J=5.2, 12.8 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.48 (t,J=5.2 Hz, 2H), 3.78 (t, J=5.2 Hz, 2H), 3.52-3.38 (m, 4H), 3.33-3.28 (m,2H), 3.03 (q, J=5 0.6 Hz, 2H), 2.95-2.82 (m, 1H), 2.63-2.52 (m, 2H),2.08-1.99 (m, 1H), 1.36 (s, 9H); LC-MS (ESI⁺) m/z 586.4 (M+H)⁺.

Step2—4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (0.30 g, 502 umol) inDCM (6 mL) was added HCl/dioxane (4 M, 2.94 mL). The mixture was stirredat 5° C. for 0.5 hour. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (0.22 g, 84% yield) asyellow solid. LC-MS (ESI⁺) m/z 486.3 (M+H)⁺.

2-(2,6-Dioxo-3-piperidyl)-5-(prop-2-ynylamino)isoindoline-1,3-dione(Intermediate IF)

To a solution of2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (700 mg, 2.53mmol, Intermediate HX) and prop-2-yn-1-amine (209 mg, 3.80 mmol) in DMSO(10 mL) was added DIPEA (983 mg, 7.60 mmol). The reaction mixture wasstirred at 130° C. for 1.5 hours. On completion, the mixture was dilutedwith water (40 mL), and extracted with DCM (2×30 mL). The organic layerswere washed with brine (40 mL), and concentrated in vacuo. The residuewas purified by silica gel chromatography to give the title compound(0.25 g, 27% yield) as a yellow solid. LC-MS (ESI⁺) m/z 312.2 (M+H)⁺.

5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate IG)

Step 1—Tert-ButylN-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(prop-2-ynylamino)isoindoline-1,3-dione (200mg, 546 umol, Intermediate IF) and tert-butylN-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (300 mg, 1.09 mmol,Intermediate ID) in a mixed solvent of H₂O (3 mL) and t-BuOH (3 mL) wasadded CuSO₄ (872 ug, 5.46 umol) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (2.16mg, 10.9 umol). The reaction mixture was stirred at 60° C. for 2 hrs. Oncompletion, the mixture was diluted with water (30 mL), and extractedwith DCM (30 mL). The organic layers were concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the titlecompound (240 mg, 75% yield) as a yellow solid. LC-MS (ESI⁺) m/z 586.1(M+H)⁺.

Step2—5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]methyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (240 mg, 410 umol) inDCM (2 mL) was added HCl/dioxane (4 mL). The reaction mixture wasstirred at 20° C. for 12 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (210 mg, 98% yield,HCl) as a yellow solid. LC-MS (ESI⁺) m/z 486.1 (M+H)⁺.

4-[2-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate IH

Step1—4-(But-3-yn-1-ylamino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (400 mg, 1.45mmol, Intermediate R) and but-3-yn-1-amine (120 mg, 1.74 mmol) indioxane (10 mL) was added DIPEA (561 mg, 4.34 mmol). The reactionmixture was stirred at 115° C. for 12 hrs. On completion, the reactionmixture was concentrated in vacuo. The crude product was purified byreversed phase (0.1% HCl condition) to give the title compound (230 mg,49% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H),7.63-7.56 (m, 1H), 7.17 (d, J=8.8 Hz, 1H), 7.06 (d, J=7.2 Hz, 1H), 6.72(t, J=6.0 Hz, 1H), 5.07 (dd, J=5.2, 12.8 Hz, 1H), 3.70 (t, J=7.0 Hz,1H), 3.48 (q, J=6.8 Hz, 2H), 2.96-2.83 (m, 3H), 2.57-2.53 (m, 2H),2.09-1.99 (m, 1H); LC-MS (ESI⁺) m/z 326.1 (M+H)⁺.

Step 2—Tert-Butyl(2-(2-(2-(5-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethoxy)ethyl)carbamate

To a solution of4-(but-3-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (280mg, 861 umol) and tert-butylN-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (472 mg, 1.72 mmol,Intermediate ID) in THF (5 mL) was added chlororuthenium (1+);1,2,3,4,5-pentamethylcyclopenta-1,3-diene; triphenylphosphane (13.7 mg,17.2 umol, CAS: 92361-49-4). The reaction mixture was stirred at 65° C.for 12 hrs under N₂. On completion, the reaction mixture was filteredand concentrated in vacuo. The crude product was purified by silica gelchromatography (EA:ACN=1:1) to give the title compound (300 mg, 57%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.40 (s, 1H),7.57-7.52 (m, 1H), 7.57-7.52 (m, 1H), 7.28 (s, 1H), 7.16 (d, J=7.2 Hz,1H), 6.93 (d, J=8.8 Hz, 1H), 6.40 (t, J=5.6 Hz, 1H), 4.92 (d, J=5.6 Hz,1H), 4.49 (t, J=5.6 Hz, 2H), 3.93 (t, J=5.6 Hz, 2H), 3.65 (q, J=7.2 Hz,2H), 3.55-3.51 (m, 4H), 3.44 (t, J=5.2 Hz, 2H), 3.27 (d, J=4.8 Hz, 2H),3.11 (t, J=7.2 Hz, 2H), 2.93-2.74 (m, 3H), 2.22-2.11 (m, 1H), 1.45 (s,9H); LC-MS (ESI⁺) m/z 600.1 (M+H)⁺.

Step3—4-[2-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (300 mg, 500umol) in DCM (5 mL) was added HCl/dioxane (4 M, 7.50 mL). The reactionmixture was stirred at 20° C. for 0.5 hr. On completion, the reactionmixture was concentrated in vacuo to give the title compound (268 mg,100% yield, HCl salt) as yellow solid. LC-MS (ESI⁺) m/z 500.1 (M+H)⁺.

4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate II)

Step 1—2-(2,6-Dioxo-3-piperidyl)-4-prop-2-ynoxy-isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione (3.00 g, 10.9mmol, synthesized via Step 1 of Intermediate CA) in DMF (30 mL) wasadded K₂CO₃ (1.66 g, 12.0 mmol). Then 3-bromoprop-1-yne (1.43 g, 12.0mmol) was added and the mixture was stirred at 20° C. for 12 hrs. Oncompletion, the mixture was diluted with water (200 mL), stirred andfiltered. The filter cake was purified by reverse phase (0.1% HClcondition) to give the title compound (0.90 g, 26% yield) as a lightyellow solid. LC-MS (ESI⁺) m/z 313.1 (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxymethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (527 mg, 1.92 mmol,Intermediate ID), CuSO₄ (1.53 mg, 9.61 umol) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (3.81mg, 19.2 umol) in a mixed solvent of H₂O (3 mL) and t-BuOH (3 mL) wasadded 2-(2,6-dioxo-3-piperidyl)-4-prop-2-ynoxy-isoindoline-1,3-dione(300 mg, 961 umol). The reaction mixture was stirred at 60° C. for 2hrs. On completion, the mixture was diluted with H₂O (20 mL), andextracted with EA (2×30 mL). The organic layer was washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by silica gel chromatography to give the title compound(460 mg, 82% yield) as a white solid. LC-MS (ESI⁺) m/z 587.3 (M+H)⁺.

Step3—4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxymethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (105 mg, 179 umol)in DCM (2 mL) was added HCl/dioxane (3 mL). The reaction mixture wasstirred at 20° C. for 1 hr. On completion, the mixture was concentratedin vacuo to give the title compound (93.0 mg, 99% yield, HCl) as a whitesolid. LC-MS (ESI⁺) m/z 487.2 (M+H)⁺.

4-[2-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate IJ)

Step 1—4-But-3-ynoxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione (1 g, 3.65mmol, synthesized via Step 1 of Intermediate CA) and but-3-yn-1-ol (307mg, 4.38 mmol, CAS #927-74-2) in THF (10 mL) was added PPh₃ (1.43 g,5.47 mmol). Then a solution of DIAD (1.47 g, 7.29 mmol, 1.42 mL, 2.0 eq)in THF (10 mL) was added into the above mixture dropwise at 0° C. Thereaction mixture was stirred at 20° C. for 12 hrs. On completion, themixture was concentrated in vacuo. The residue was purified by reversephase (0.10% HCl condition) to give the title compound (0.7 g, 59%yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 11.12 (s, 1H),7.86-7.76 (m, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 5.08(dd, J=5.2, 12.8 Hz, 1H), 4.31 (t, J=6.8 Hz, 2H), 2.92 (t, J=2.8 Hz,1H), 2.90-2.80 (m, 1H), 2.75-2.66 (m, 2H), 2.64-2.52 (m, 2H), 2.09-1.97(m, 1H).

Step 2—Tert-ButylN-[2-[2-[2-[5-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyethyl]triazol-1-yl]]ethoxy]ethyl]carbamate

To a solution of4-but-3-ynoxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.25 g,766 umol) and tert-butyl N-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate(420 mg, 1.53 mmol, Intermediate ID) in THF (8 mL) was addedchlororuthenium (1+); 1,2,3,4,5-pentamethylcyclopenta-1,3-diene;triphenylphosphane (30.5 mg, 38.3 umol, CAS #92361-49-4). The reactionmixture was stirred at 65° C. for 15 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography (SiO₂) to give the title compound (330 mg, 68% yield) asa white solid. LC-MS (ESI⁺) m/z 601.2 (M+H)⁺.

Step3—4-[2-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[5-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (330 mg, 522 umol)in DCM (2 mL) was added HCl/dioxane (4 mL). The reaction mixture wasstirred at 20° C. for 12 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (280 mg, 100% yield,HCl) as an off-white solid. LC-MS (ESI⁺) m/z 501.1 (M+H)⁺.

2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl methanesulfonate(Intermediate IK)

Step 1—Benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate

To a solution of 2-(2-aminoethoxy)ethanol (5.00 g, 47.5 mmol, 4.76 mL,CAS #929-06-6) and NaHCO₃ (11.9 g, 142 mmol, 5.55 mL) in MeCN (50 mL)and H₂O (50 mL) was added CbzCl (9.74 g, 57.07 mmol, 8.11 mL) dropwiseat 0° C. The reaction mixture was stirred at 20° C. for 12 hours. Oncompletion, the mixture was filtered, the filtrate was extracted with EA(2×100 mL), and the organic phase was concentrated in vacuo to give aresidue. The residue was purified by flash silica gel chromatography togive the title compound (10.0 g, 87.9% yield) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.38-7.29 (m, 5H), 5.55 (s, 1H), 5.10 (s, 2H), 3.73-3.69(m, 2H), 3.57-3.51 (m, 4H), 3.40 (q, J=5.2 Hz, 2H), 2.84 (s, 1H).

Step 2—2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl methanesulfonate(3)—Notebook Page: EW5765-602, EW5765-605

To a solution of benzyl N-[2-(2-hydroxyethoxy)ethyl]carbamate (1 g, 4.18mmol) and TEA (1.27 g, 12.5 mmol, 1.75 mL) in DCM (10 mL) was added MsCl(574 mg, 5.02 mmol, 388 uL) at 0° C. The reaction mixture was stirred at20° C. for 1 hour. On completion, the mixture was quenched with theaddition of H₂O (30 mL), then exacted with DCM (2×50 mL). The organicphase was concentrated in vacuo to give a title compound (1.30 g, 98%yield) as yellow oil. LC-MS (ESI⁺) m/z 318.2 (M+H)⁺.

Benzyl N-[2-(2-piperazin-1-ylethoxy)ethyl]carbamate (Intermediate IL)

Step 1—Tert-Butyl4-(2-(2-(((benzyloxy)carbonyl)amino)ethoxy)ethyl)piperazine-1-carboxylate

To a solution of 2-[2-(benzyloxycarbonylamino)ethoxy]ethylmethanesulfonate (6.6 g, 20.8 mmol) and tert-butylpiperazine-1-carboxylate; hydrochloride (4.49 g, 17.3 mmol, HCl, CAS#57260-71-6) in MeCN (100 mL) was added KI (287 mg, 1.73 mmol) andNaHCO₃ (4.37 g, 51.9 mmol, 2.02 mL). The reaction mixture was stirred at80° C. for 16 hours. On completion, the mixture was filtered, and thefiltrate was concentrated in vacuo to give a residue. The residue waspurified by column chromatography to give the title compound (5.00 g,71% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.28 (m, 5H),5.58 (s, 1H), 5.30 (s, 1H), 5.10 (s, 2H), 3.58 (t, J=5.6 Hz, 2H),3.56-3.50 (m, 2H), 3.47-3.33 (m, 6H), 2.55 (t, J=5.6 Hz, 2H), 2.42 (m,J=4.8 Hz, 4H), 1.46 (s, 9H).

Step 2—Benzyl N-[2-(2-piperazin-1-ylethoxy)ethyl]carbamate

To a solution of tert-butyl4-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]piperazine-1-carboxylate(5.00 g, 12.2 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 25 mL).The reaction mixture was stirred at 25° C. for 3 hours. On completion,the mixture was concentrated in vacuo to give the title compound (3.80g, 90% yield) as a yellow solid. LC-MS (ESI⁺) m/z 308.3 (M+H)⁺.

Tert-ButylN-[2-[2-[4-[2-(2-aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate(Intermediate IM)

Step 1—Tert-ButylN-[2-[2-[4-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate

To a solution of benzyl N-[2-(2-piperazin-1-ylethoxy)ethyl]carbamate(2.00 g, 6.51 mmol, Intermediate IL) in THF (50 mL) was added TEA (1.32g, 13.0 mmol, 1.81 mL). The mixture was stirred at 25° C. for 30 min,then tert-butyl N-[2-(2-oxoethoxy)ethyl]carbamate (1.85 g, 9.11 mmol,synthesized via Step 1 of Intermediate FS), HOAc (1.17 g, 19.5 mmol,1.12 mL) and NaBH(OAc)₃ (2.76 g, 13.0 mmol) was added in the mixture.The reaction mixture was stirred at 25° C. for 24 hours. On completion,the reaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (2.00 g, 62% yield) as yellow oil. LC-MS (ESI⁺) m/z 495.4(M+1)⁺.

Step 2—Tert-ButylN-[2-[2-[4-[2-(2-aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[4-[2-[2-(benzyloxycarbonylamino)ethoxy]ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate (1.00 g, 2.02 mmol) in THF (5 mL) was added Pd/C(500 mg, 202 umol, 10 wt %). The reaction mixture was stirred at 20° C.under H₂ (15 psi) for 24 hours. On completion, the residue was filteredand the filtrate was concentrated in vacuo to give the title compound(600 mg, 82% yield) as colorless oil. LC-MS (ESI⁺) m/z 361.3 (M+H)⁺.

4-[2-[2-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate IN

Step 1—Tert-ButylN-[2-[2-[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[4-[2-(2-aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate(300 mg, 832 umol, Intermediate IM) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (229 mg, 832umol, Intermediate R) in DMSO (10 mL) was added DIPEA (537 mg, 4.16mmol, 724 uL). The reaction mixture was stirred at 90° C. for 2 hours.On completion, the mixture was diluted with H₂O (30 mL), then extractedwith DCM (2×60 mL). The combined organic phase was washed with brine,and then concentrated in vacuo to give a residue. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(200 mg, 39% yield) as a yellow solid. LC-MS (ESI⁺) m/z 617.4 (M+H)⁺.

Step2—4-[2-[2-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate (200 mg, 324umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL), and the reactionmixture was stirred at 25° C. for 1 hour. On completion, the mixture wasconcentrated in vacuo to give the title compound (150 mg, 83% yield) asa yellow solid. LC-MS (ESI⁺) m/z 517.3 (M+H)⁺.

4-[2-[2-[6-[2-(2-Aminoethoxy)ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate IO)

Step 1—Tert-Butyl6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate(0.40 g, 1.70 mmol, HCl, CAS #1041026-70-3) and2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethanesulfonate (899 mg, 2.04 mmol, synthesized via Steps 1-2 ofExample 184) in CH₃CN (80 mL) was added NaHCO₃ (429 mg, 5.11 mmol). Themixture was stirred at 80° C. for 6 hr. On completion, the mixture wasconcentrated. The residue was purified by flash silica gelchromatography (DCM:MeOH=10:1) to give the title compound (0.80 g, 69%yield, 80% purity) as a yellow solid. LC-MS (ESI⁺) m/z 542.4 (M+H)⁺.

Step2—4-[2-[2-(2,6-Diazaspiro[3.3]heptan-2-yl)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butyl6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.80 g, 1.48mmol) in DCM (50 mL) was added TFA (6.16 g, 54.0 mmol). The mixture wasstirred at 15° C. for 5 min. On completion, the mixture wasconcentrated. The crude product was purified by reversed-phasechromatography (0.1% FA condition) to give the title compound (0.34 g,47% yield, FA salt) as a yellow solid. LC-MS (ESI⁺) m/z 442.3 (M+H)⁺.

Step 3—Tert-ButylN-[2-[2-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethyl]carbamate

To a solution of4-[2-[2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (0.29 g, 595 umol, FA) and tert-butylN-[2-(2-oxoethoxy)ethyl]carbamate (363 mg, 1.78 mmol, synthesized viaStep 1 of Intermediate FS) in DCM (1 mL) and THF (1 mL) was added Et₃N(181 mg, 1.78 mmol) and AcOH (71.5 mg, 1.19 mmol) and then addedNaBH(OAc)₃ (252 mg, 1.19 mmol). The mixture was stirred at 15° C. for 6hrs. On completion, the mixture was concentrated. The crude product waspurified by reversed-phase chromatography (0.1% FA condition) to givethe title compound (0.32 g, 68% yield, 80% purity) as a yellow solid.LC-MS (ESI⁺) m/z 629.4 (M+H)⁺.

Step4—4-[2-[2-[6-[2-(2-Aminoethoxy)ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]ethyl]carbamate(0.22 g, 350 umol) in DCM (2 mL) was added TFA (39.9 mg, 350 umol). Themixture was stirred at 15° C. for 0.5 hr. On completion, the mixture wasconcentrated to give the title compound (0.10 g, 310% yield, 70% purity,TFA) as yellow oil. LC-MS (ESI⁺) m/z 529.4 (M+H)⁺.

5-Bromo-3-methyl-1H-benzimidazol-2-one (Intermediate IP)

Step 1—5-Bromo-N-methyl-2-nitro-aniline

4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS #321-23-3) wasadded to a solution of methylamine in tetrahydrofuran (2 M, 1.51 L). Themixture was stirred at 15° C. for 10 minutes. On completion, the mixturewas diluted with H₂O (250 mL) and extracted with EtOAc (3×300 mL). Thecombined organic layers were washed with brine (300 mL), dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(200 g, 83% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.22(s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 6.82 (dd,J=8.4, 1.6 Hz, 1H), 2.95 (d, J=4.8 Hz, 3H).

Step 2—4-Bromo-N2-methyl-benzene-1,2-diamine

To a mixture of 5-bromo-N-methyl-2-nitro-aniline (200 g, 865 mmol) inEtOAc (1 L) and H₂O (500 mL) was added AcOH (1.00 L). The mixture waswarmed to 50° C., and then Fe (174 g, 3.11 mol) was added to thereaction mixture. After that, the reaction mixture was stirred at 80° C.for 6 hours. On completion, the mixture was filtered through celite. Thefiltrate was concentrated in vacuo and the residue was diluted with H₂O(250 mL) and extracted with EtOAc (3×300 mL). The combined organiclayers were washed with aq.NaHCO₃ and brine (300 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashsilica gel chromatography to give the title compound (130 g, 75% yield)as black oil. ¹H NMR (400 MHz, DMSO-d₆) δ 6.55-6.52 (m, 1H), 6.48-6.45(m, 1H), 6.43-6.42 (m, 1H), 4.89-4.88 (m, 1H), 4.61 (s, 2H), 2.70 (d,J=4.0 Hz, 3H).

Step 3—5-Bromo-3-methyl-1H-benzimidazol-2-one

To a solution of 4-bromo-N2-methyl-benzene-1,2-diamine (110 g, 547 mmol)in CH₃CN (1.3 L) was added CDI (177 g, 1.09 mol). The mixture wasstirred at 80° C. for 6 hours under N₂. On completion, the mixture wasconcentrated in vacuo. The mixture was diluted with H2O (1.0 L) andfiltered. The filter cake was washed with water (3×200 mL) and dried invacuo to give the title compound (106 g, 85% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.33 (s, 1H), 7.13 (d, J=8.0 Hz,1H), 6.92 (d, J=8.0 Hz, 1H), 3.27 (s, 3H).

[1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (IntermediateIO)

Step 1—5-Oxotetrahydrofuran-2-carboxylic Acid

To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS#617-65-2) in H₂O (800 mL) and HCl (12 M, 210 mL) was added a solutionof NaNO₂ (147 g, 2.13 mol) in H2O (400 mL) at −5° C. The mixture wasstirred at 15° C. for 12 hrs. On completion, the mixture wasconcentrated and then dissolved in EA (500 mL) and filtered and washedwith EA (3×100 mL). The filtrate and washed solution were dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(200 g, crude) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.43 (s, 1H),5.02-4.95 (m, 1H), 2.67-2.38 (m, 4H)

Step 2—N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide

To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was addedSOCl₂ (246 g, 2.07 mol) at 0° C. slowly. The mixture was stirred at 85°C. for 3 hrs, and then the mixture was stirred at 15° C. for 6 hrs. Themixture was concentrated in vacuo. The residue was dissolved in dry DCM(1 L) at 0° C. under N₂. After that a solution of Et₃N (187 g, 1.84 mol)and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added,then the mixture was stirred at 15° C. for 3 hrs. On completion, water(600 mL) was added and the mixture was extracted with DCM (3×300 mL).The combined organic phase was washed with 0.5 M HCl (500 mL), brine(500 mL), dried over with anhydrous sodium sulfate and filtered. Thefiltrate was concentrated in vacuo and the residue was purified by flashsilica gel chromatography (PE:EA=1:1) to give the title compound (138 g,60% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.22-7.20 (d,J=8.0, 1H), 6.89-6.87 (d, J=8.0, 1H), 4.90-4.86 (m, 1H), 4.47-4.4.36 (m,2H) 3.81 (s, 3H), 2.67-2.64 (m, 1H), 2.59-2.54 (m, 2H), 2.40-2.38 (m,1H); LC-MS (ESI⁺) m/z 272.0 (M+Na)⁺.

Step 3—3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

A solution ofN-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g,553 mmol) in anhydrous THF (1500 mL) was cooled to −78° C. Then, t-BuOK(62.7 g, 559 mmol) in a solution of anhydrous THF (1000 mL) was addeddropwise slowly at −78° C. under nitrogen atmosphere. The resultingreaction mixture was stirred at −40° C. for 1 hr. On completion, thereaction mixture was quenched with saturated NH₄Cl solution (100 mL).The mixture was extracted with ethyl acetate (3×1500 mL). The combinedorganic layer was washed with brine (300 mL), dried over anhydroussodium sulfate, filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatography (PE:EA=1:1) to givethe title compound (128 g, 92% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.39-7.32 (m, 2H), 6.89-6.81 (m, 2H), 4.91 (s, 2H), 4.17-4.11(m, 1H), 3.80 (s, 3H), 3.54 (s, 1H), 2.98-2.87 (m, 1H), 2.73-2.60 (m,1H), 2.26-2.20 (m, 1H), 1.80 (dq, J=4.8, 13.1 Hz, 1H).

Step 4—[1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate

To a solution of 3-hydroxy-1-[(4-methoxyphenyl) methyl] piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (73.0 g,258 mmol) dropwise at 0° C. The mixture was stirred at −10° C. for 1.5hours under N₂. On completion, the mixture was concentrated in vacuo.The residue was purified by column chromatography on silica gel(PE:EA=20:1/8:1) to give the title compound (45.0 g, 68% yield) as lightyellow gum. ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J=8.4 Hz, 2H), 6.85-6.82(m, 2H), 5.32-5.28 (m, 1H), 4.91 (s, 2H), 3.79 (s, 3H), 3.02-2.97 (m,1H), 2.79-2.74 (m, 1H), 2.41-2.35 (m, 2H).

3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate IR)

Step 1: 3-bromo-2-(bromomethyl) benzoate

To a solution of methyl 3-bromo-2-methylbenzoate (10.0 g, 43.64 mmol,CAS #: 99548-54-6) in benzene (60 ml) were added N-bromosuccinimide (6.1g, 52.37 mmol) and benzoyl peroxide (1.05 g, 4.36 mmol) at rt. Thereaction mixture was stirred at 80° C. for 12 h. The resulting reactionmixture was poured into EtOAc (260 mL) and the organic layer was washedwith water (200 ml), separated, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to give the residue. The crude waspurified by flash chromatography (eluting at 0-2% ethyl acetate inhexane) to afford 3-bromo-2-(bromomethyl) benzoate (12.0 g, 39.33 mmol).¹H NMR (400 MHz, DMSO-d6) δ 7.92 (dd, J=8.0, 1.3 Hz, 1H), 7.85 (dd,J=7.8, 1.3 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 5.02 (s, 2H), 3.87 (s, 3H).

Step 2: 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

To a solution of 3-bromo-2-(bromomethyl) benzoate (12.0 g, 39.33 mmol)in ACN (100 ml) were added 3-aminopiperidine-2,6-dione hydrochloride(7.76 g, 47.20 mmol, CAS #: 24666-56-6), TEA (11.95 g, 117.9 mmol) atrt. The reaction mixture was heated 80° C. for 12 h then cooled to rt.EtOAc (250 ml) was added and the organic layer was washed with water(500 ml), separated, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The obtained crude material was purified by flash chromatography(eluting at 4-6% Methanol in DCM) to give3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (5.60 g, 17.33mmol). LCMS m/z: (ES+) 323.0 (M+1)⁺. ¹H NMR (400 MHz, DMSO-d6) δ 11.04(s, 1H), 7.88 (dd, J=7.9, 0.9 Hz, 1H), 7.78 (dd, J=7.5, 0.9 Hz, 1H),7.52 (t, J=7.7 Hz, 1H), 5.16 (dd, J=13.3, 5.1 Hz, 1H), 4.43 (d, J=17.6Hz, 1H), 4.27 (d, J=17.7 Hz, 1H), 2.92 (ddd, J=17.2, 13.7, 5.4 Hz, 1H),2.61 (dd, J=17.5, 4.3 Hz, 1H), 2.02 (dtd, J=12.8, 5.4, 2.3 Hz, 1H).

Tert-Butyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate(Intermediate IS)

To a stirred solution of tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (1.0 g, 4.01 mmol,synthesized via Step 1 on Intermediate AC) in THF (50 ml) was added NaH(0.2 g, 4.81 mmol) at 0-5° C. 3-bromoprop-1-yne (0.9 ml, 6.02 mmol, CAS#: 106-96-7) was added dropwise at 0-5° C. The reaction mixture wasstirred at rt for 5 h. The resulting reaction mixture was poured intoice cold water (200 ml) and extracted with ethyl acetate (3×200 ml). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated under vacuum to afford tert-butyl(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate (1.1 g, 3.83mmol). LCMS m/z (ES+): 188.2 (M−99)⁺.

Tert-Butyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (IntermediateIT)

To a stirred solution of tert-butyl (2-(2-hydroxyethoxy)ethyl)carbamate(2.0 g, 9.74 mmol, CAS #: 139115-91-6) in THF (50 ml) was added NaH(0.47 g, 11.70 mmol) at 0-5° C. 3-bromoprop-1-yne (2.1 ml, 14.62 mmol)was added dropwise at 0-5° C. The reaction mixture was stirred at rt for5 h. The resulting reaction mixture was poured into ice cold water (200ml) and extracted with ethyl acetate (3×200 ml). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum to afford tert-butyl(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (2.1 g, 8.97 mmol). LCMSm/z: (ES+) 144.1 (M−99)⁺.

Tert-Butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (Intermediate IU)

To a stirred solution of tert-butyl (2-hydroxyethyl)carbamate (3.70 g,22.96 mmol, CAS #: 26690-80-) in THF (150 ml) was added NaH (1.1 g,27.55 mmol) at 0-5° C. Then 3-bromoprop-1-yne (3.3 ml, 34.44 mmol) wasadded dropwise at 0-5° C. The reaction mixture was stirred at rt for 3h. The resulting reaction mixture was poured into ice cold water (200ml) and extracted with ethyl acetate (3×100 ml). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum to afford crude material. The isolated crude material was furtherpurified by column chromatography (eluting at 15% ethyl acetate inhexane) to afford tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (4.12g, 20.69 mmol). ¹H NMR (400 MHz, DMSO-d6) δ 6.83 (t, J=5.8 Hz, 1H), 4.12(d, J=2.4 Hz, 2H), 3.42 (s, 2H), 3.08 (q, J=6.0 Hz, 2H), 1.38 (s, 9H).

2-(1-Methylpyrazol-4-yl)oxazole-4-carboxylic Acid (Intermediate IV)

Step 1—Ethyl 2-(1-methylpyrazol-4-yl)oxazole-4-carboxylate

To a solution of ethyl 2-chlorooxazole-4-carboxylate (1.87 g, 10.7 mmol,CAS #4600081-18-9) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2.22g, 10.7 mmol, CAS #761446-44-0) in a mixed solvent of H₂O (6 mL) anddioxane (30 mL) was added K₂CO₃ (2.94 g, 21.3 mmol) and Pd(dppf)Cl₂CH₂Cl₂ (870 mg, 1.07 mmol). The reaction mixture was stirred at 80° C.for 4 hours under nitrogen. On completion, the reaction mixture wasdiluted with EA (100 mL) and filtered. The organic layers were driedwith anhydrous Na₂SO₄, and concentrated in vacuo. The residue waspurified by silica column chromatography (SiO₂) to give the titlecompound (1.50 g, 64% yield) as a white solid. LC-MS (ESI⁺) m/z 222.1(M+H)⁺.

Step 2—2-(1-Methylpyrazol-4-yl)oxazole-4-carboxylic Acid

To a solution of ethyl 2-(1-methylpyrazol-4-yl)oxazole-4-carboxylate(1.20 g, 5.42 mmol) in THF (30 mL) was added a solution of LiOH H₂O (683mg, 16.3 mmol) in H₂O (6 mL). The reaction mixture was stirred at 25° C.for 12 hours. On completion, the reaction mixture was diluted with water(50 mL), acidified with HCl (1N, 10 mL), and filtered. The filter cakewas washed with water (2×10 mL) and dried in vacuo to give the titlecompound (1.10 g, 80% purity) as a white solid.

N-[3-(difluoromethyl)-1-(4-formylphenvl)pyrazol-4-yl]-2-(1-methylpyrazol-4-yl)oxazole-4-carboxamide(Intermediate IW)

Step 1—Methyl4-[3-(difluoromethyl)-4-[[2-(1-methylpyrazol-4-yl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

To a solution of 2-(1-methylpyrazol-4-yl)oxazole-4-carboxylic acid (860mg, 4.45 mmol, Intermediate IV) and methyl4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate (833 mg, 3.12 mmol,Intermediate FW) in DMF (30 mL) was added DIPEA (2.30 g, 17.8 mmol) andHATU (1.86 g, 4.90 mmol). The reaction mixture was stirred at 25° C. for1 hour. On completion, the reaction mixture was poured into water (50mL), and filtered to give the filter cake. The cake was washed withwater (2×20 mL) and dried in vacuo to give the title compound (1.40 g,68% yield) as a white solid. LC-MS (ESI⁺) m/z 443.2 (M+H)⁺.

Step2—4-[3-(Difluoromethyl)-4-[[2-(1-methylpyrazol-4-yl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid

To a solution of methyl4-[3-(difluoromethyl)-4-[[2-(1-methylpyrazol-4-yl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate (800 mg, 1.81 mmol) in THF (10 mL) was added asolution of LiOH H₂O (228 mg, 5.43 mmol) in H₂O (2 mL). The reactionmixture was stirred at 40° C. for 12 hours. On completion, the reactionmixture was quenched with HCl (1N, 3 mL) and concentrated in vacuo togive the title compound (900 mg, 59% purity) as a white solid. LC-MS(ESI⁺) m/z 429.0 (M+H)⁺.

Step3—N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(1-methylpyrazol-4-yl)oxazole-4-carboxamide

To a solution of4-[3-(difluoromethyl)-4-[[2-(1-methylpyrazol-4-yl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoic acid (775 mg, 1.81 mmol) and TEA (732 mg, 7.24mmol) in THF (30 mL) was added isopropyl carbonochloridate (443 mg, 3.62mmol) at −10° C. The reaction mixture was stirred at −10° C. for 2hours. After that, H₂O (3 mL) was added. The reaction mixture was warmedto 0° C. Then LiBH₄ (158 mg, 7.24 mmol) was added slowly. The reactionmixture was stirred at 0° C. for 2 hours. On completion, the reactionmixture was diluted with THF (50 mL) and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by silica columnchromatography (SiO₂) to give the title compound (200 mg, 27% yield) asa white solid. LC-MS (ESI⁺) m/z 415.2 (M+H)⁺.

Step4—N-[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]-2-(1-methylpyrazol-4-yl)oxazole-4-carboxamide

To a solution ofN-[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(1-methylpyrazol-4-yl)oxazole-4-carboxamide(180 mg, 434 umol) in THF (20 mL) was added DMP (184 mg, 434 umol). Thereaction mixture was stirred at 25° C. for 12 hours. On completion, thereaction mixture was quenched with water (5 mL) and concentrated invacuo. The residue was dissolved in EA (200 mL), washed with water (50mL), sat.NaHCO₃ (50 mL), and brine (50 mL). The organic layer was driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (200 mg, 710% yield) as a white solid. LC-MS (ESI⁺) m/z413.1 (M+H)⁺.

5-[2-[2-(2-Aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate IX)

Step 1—Tert-ButylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethoxy]ethyl]carbamate

To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione(100 mg, 362 umol, Intermediate HX) and tert-butylN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (107 mg, 434 umol, CAS#153086-78-3) in DMSO (5 mL) was added DIPEA (233 mg, 1.81 mmol, 315uL). The reaction mixture was stirred at 130° C. for 1 hour. Oncompletion, the reaction mixture was diluted with water (20 mL) andextracted with EA (3×30 mL). The combined organic layers was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (0.1% FA condition) to give the titlecompound (90.0 mg, 49% yield) as light yellow solid. LC-MS (ESI⁺) m/z505.1 (M+H)⁺.

Step2—5-[2-[2-(2-Aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethoxy]ethyl]carbamate (90.0 mg, 178 umol) in DCM (5 mL) wasadded HCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 20°C. for 1 hour. On completion, the reaction mixture was concentrated invacuo to give the title compound (72.0 mg, 91% yield, HCl) as lightyellow solid. LC-MS (ESI⁺) m/z 405.3 (M+H)⁺.

Tert-Butyl N-methyl-N-prop-2-ynyl-carbamate (Intermediate IY)

To a solution of tert-butyl N-methylcarbamate (10.4 g, 79.2 mmol) in THF(120 mL) was added NaH (4.12 g, 103 mmol, 60% purity) under 0° C. Themixture was stirred at 0° C. for 0.5 hour, then 3-bromoprop-1-yne (13.2g, 111 mmol) was added dropwise. The mixture was stirred at rt for 16hours. On completion, the reaction mixture was quenched with water (10mL) at 0° C., and then concentrated in vacuo to give a residue. Theresidue was diluted with water (80 mL) and extracted with DCM (4×60 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography to give the title compound (4.50 g, 33% yield) aslight yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.05 (s, 2H), 2.92 (s,3H), 2.22 (t, J=2.4 Hz, 1H), 1.47 (s, 9H).

2-(2,6-Dioxo-3-piperidyl)-4-[3-(methylamino)propyl]isoindoline-1,3-dione(Intermediate IZ)

Step 1—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynyl]-N-methyl-carbamate

To a solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1.87 g, 5.54 mmol, Intermediate FT) and tert-butylN-methyl-N-prop-2-ynyl-carbamate (1.5 g, 8.86 mmol, Intermediate IY) inDMF (5 mL) was added Pd(PPh₃)₂Cl₂ (388 mg, 554 umol), TEA (10.0 g, 99.7mmol) and CuI (105 mg, 554 umol). The mixture was heated at 80° C. for30 minutes under microwave. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (PE:EA=1:1) to give the title compound (1.90g, 71% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13(s, 1H), 7.93-7.89 (m, 1H), 7.89-7.84 (m, 2H), 5.15 (dd, J=5.4, 12.8 Hz,1H), 4.37 (s, 2H), 3.32 (s, 3H), 3.01-2.90 (m, 3H), 2.90-2.82 (m, 1H),2.64-2.51 (m, 2H), 2.11-2.00 (m, 1H), 1.47-1.36 (m, 9H); LC-MS (ESI⁺)m/z 448.2 (M+Na)⁺.

Step 2—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propyl]-N-methyl-carbamate

To a solution of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynyl]-N-methyl-carbamate(0.50 g, 1.05 mmol) in THF (20 mL) was added Pd/C (0.2 g, 1.05 mmol, 10wt %) and Pd(OH)₂/C (0.2 g, 1.05 mmol, 10% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ three times. Themixture was stirred under H₂ (15 Psi) at 20° C. for 2 hours. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (0.4 g, 89% yield) asblack brown solid. LC-MS (ESI⁺) m/z 452.3 (M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-4-[3-(methylamino)propyl]isoindoline-1,3-dione

To a solution of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propyl]-N-methyl-carbamate(0.40 g, 828 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 4 mL). Themixture was stirred at 5° C. for 20 minutes. On completion, the reactionmixture was concentrated in vacuo to give the title compound (0.28 g,92% yield) as black brown solid. LC-MS (ESI⁺) m/z 330.2 (M+H)⁺.

N-[3-carbamoyl-1-(4-formylphenvl)pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide(Intermediate JA)

Step 1—Isopropoxycarbonyl4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

To a mixture of4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicacid (500 mg, 1.20 mmol, Intermediate EE) in THF (20 mL) was added TEA(483 mg, 4.78 mmol, 665 uL) and isopropyl carbonochloridate (366 mg,2.99 mmol, 414 uL). The reaction mixture was stirred at −10° C. for 2hours. On completion, the reaction mixture was filtered. The filtratewas concentrated to give the title compound (600 mg, 99% yield) as lightyellow oil. LC-MS (ESI⁺) m/z 505.0 (M+H)⁺.

Step2—N-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

To a mixture of isopropoxycarbonyl4-[3-carbamoyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate (600 mg, 1.19 mmol) in H₂O (5 mL) and THF (50 mL)was added LiBH₄ (155 mg, 7.14 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 2 hours. On completion, the reaction mixture wasquenched with water (30 mL) under stirring. Then the mixture wasextracted with EA (3×50 mL). The combined organic layers was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was triturated with DCM/PE (5 mL/30 mL) and filtered to give thetitle compound (250 mg, 51% yield) as light yellow solid. LC-MS (ESI⁺)m/z 405.2 (M+H)⁺.

Step3—N-[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

To a mixture ofN-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide(250 mg, 618 umol) in DCM (10 mL) and THF (10 mL) was added DMP (524 mg,1.24 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2hours. On completion, the reaction mixture was diluted with Na₂S2O₃ (10mL), NaHCO₃ (10 mL) and stirred for 30 min. Then the mixture wasextracted with DCM (3×10 mL) and the combined organic layers was driedover Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (230 mg, 92% yield) as light yellow solid. LC-MS (ESI⁺) m/z403.2 (M+H)⁺.

[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]methanol (IntermediateJB)

To a solution of methyl4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate (1.30 g, 4.86 mmol,Intermediate FW) in a mixed solvent of THF (40 mL) was added LiAlH₄ (369mg, 9.73 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Themixture was quenched with water (0.8 mL) and NaOH aqueus solution (15%,0.8 mL) at 0° C., then filtered and dried over Na₂SO₄, filtered againand concentrated in vacuo to give the title compound (1.10 g, 94% yield)as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (s, 1H), 7.67(d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 7.05 (t, J=13.6 Hz, 1H), 5.25(t, J=5.6 Hz, 1H), 4.51 (d, J=5.6 Hz, 2H), 4.39 (s, 2H).

Tert-ButylN-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate JC)

Step 1—Tert-ButylN-[4-[4-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (1.42 g, 3.68 mmol, Intermediate CM) and HATU (1.92 g, 5.06 mmol)in DMF (20 mL) was added DIPEA (1.78 g, 13.7 mmol) and[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]methanol (1.1 g, 4.60mmol, Intermediate JB). The mixture was stirred at 25° C. for 2 hours.On completion, the reaction mixture was diluted with 80 mL water,filtered to give the filter cake and was dried in vacuo to give theproduct (1.90 g, 67% yield) as gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.06 (s, 1H), 9.07 (s, 1H), 8.80 (s, 1H), 8.65 (d, J=5.2 Hz, 1H), 8.31(s, 1H), 7.87-7.77 (m, 3H), 7.48 (d, J=8.4 Hz, 2H), 7.28 (d, J=14.4 Hz,1H), 5.30 (t, J=5.6 Hz, 1H), 4.90 (q, J=9.2 Hz, 2H), 4.56 (d, J=5.6 Hz,2H), 1.52 (s, 9H).

Step 2—Tert-ButylN-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(1.90 g, 3.12 mmol) in a THF (60 mL) was added DMP (1.59 g, 3.75 mmol).The mixture was stirred at 20° C. for 12 hours. On completion, thereaction mixture was quenched by saturated Na₂S₂O₃ (20 mL) and saturatedNaHCO₃ (20 mL) at 25° C. The mixture was stirred for 30 minutes, thenextracted with CH₂Cl₂ (3×100 mL). The combined organic layers dried overNa₂SO₄, filtered and concentrated in vacuo to give the title compound(1.30 g, 68% yield) as gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s,1H), 10.05 (s, 1H), 9.09 (s, 1H), 8.99 (s, 1H), 8.65 (d, J=5.2 Hz, 1H),8.31 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.4 Hz, 2H), 7.80 (dd,J=0.8, 5.2 Hz, 1H), 7.33 (t, J=14.0 Hz, 1H), 4.90 (q, J=8.8 Hz, 2H),1.52 (s, 9H); LC-MS (ESI⁺) m/z 607.1 (M+H)⁺.

N-[3-(difluoromethyl)-1-(4-formylphenvl)pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide(Intermediate JD)

Step1—N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

To a solution of 2-(4-pyridyl)oxazole-4-carboxylic acid (1.27 g, 6.69mmol, Intermediate ED) and HATU (3.18 g, 8.36 mmol) in DMF (60 mL) wasadded DIPEA (3.24 g, 25.0 mmol) and [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]methanol (2 g, 8.36 mmol, Intermediate JB). Themixture was stirred at 25° C. for 2 hours. On completion, the reactionmixture was diluted with water (80 mL), filtered to give the filter cakeand dried in vacuo to give the title compound (3.00 g, 87% yield) asgray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H), 9.04 (s, 1H),8.83 (d, J=6.0 Hz, 2H), 8.78 (s, 1H), 7.97 (d, J=6.0 Hz, 2H), 7.82 (d,J=8.8 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 7.29 (t, J=54 Hz, 1H), 5.30 (t,J=5.2 Hz, 1H), 4.56 (d, J=4.8 Hz, 2H).

Step2—N-[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

To a solution ofN-[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide (2.50 g, 6.08 mmol) in THF (160 mL) was added DMP(3.09 g, 7.29 mmol). The mixture was stirred at 20° C. for 12 hours. Oncompletion, the reaction mixture was quenched with saturated Na₂S₂O₃ (20mL) and saturated NaHCO₃ (20 mL) at 25° C., and then stirred for 30minutes. The mixture was then extracted with CH₂Cl₂ (3×100 mL). Thecombined organic layers dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (1.80 g, 73% yield) as gray solid.LC-MS (ESI⁺) m/z 410.2 (M+H)⁺.

4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicAcid (Intermediate JE)

Step 1—Methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate

To a solution of methyl4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate (340 mg, 1.27 mmol,Intermediate FW) and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (493 mg, 1.27 mmol, Intermediate CM) in DMF (8 mL) was added DIPEA(658 mg, 5.09 mmol) and HATU (581 mg, 1.53 mmol). The reaction mixturewas stirred at 20° C. for 1 hour. On completion, the mixture wasquenched with water (80 mL), stirred and filtered. The filter cake wasdried in vacuo to give the title compound (0.7 g, 86% yield) as anoff-white solid. LC-MS (ESI⁺) m/z 637.3 (M+H)⁺.

Step2—4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoic Acid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate (0.70g, 1.10 mmol) in a mixed solvent of THF (10 mL) and H₂O (2 mL) was addedLiOH (132 mg, 5.50 mmol). The reaction mixture was stirred at 20° C. for2 days. On completion, the mixture was acidified with 0.5 N HCl solutionuntil the pH=3-4, then stirred and filtered. The filter cake was driedin vacuo to give the title compound (0.68 g, 99% yield) as a whitesolid. LC-MS (ESI⁺) m/z 623.2 (M+H)⁺.

3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (IntermediateJF

Step1—3-(3-bromo-2-hydroxyphenylamino)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (145mg, 0.77 mmol, Intermediate LJ) in EtOH (10 mL) was added2-amino-6-bromophenol (200 mg, 0.64 mmol) and at r.t. The reactionmixture was heated and stirred under microwave irradiation at 140° C.for 25 mins. The reaction mixture was concentrated under reducedpressure. The residue was purified via reverse phase columnchromatography (ACN/H₂O with 0.1% TFA) to give title compound (80 mg,30% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (s, 1H),7.18 (d, J=8.6 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 6.75 (dd, J=6.9, 2.6 Hz,1H), 6.67-6.59 (m, 2H), 5.48 (d, J=7.1 Hz, 1H), 4.76 (q, J=14.3 Hz, 2H),4.58-4.40 (m, 1H), 3.71 (s, 3H), 3.05-2.89 (m, 1H), 2.83-2.61 (m, 1H),2.25-2.10 (m, 1H), 2.02-1.97 (m, 1H). LC-MS (ESI⁺): m/z 421.1 (M+H)⁺.

Step2—3-(7-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of3-(3-bromo-2-hydroxyphenylamino)-1-(4-methoxybenzyl)piperidine-2,6-dione(80 mg, 0.19 mmol) in THF (5 mL) was added a solution of CDI (46 mg,0.284 mmol) in THF (5 mL) at r.t. under N₂. The reaction mixture wasstirred at 35° C. for 12 h. The reaction mixture was then concentratedunder reduced pressure and the residue was purified via columnchromatography (Petroleum ether/EtOAc=2/1) to give title compound (70mg, 74% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.39 (dd,J=8.0, 1.1 Hz, 1H), 7.23-7.16 (m, 4H), 6.86 (d, J=8.7 Hz, 2H), 5.56 (dd,J=13.3, 5.3 Hz, 1H), 4.89-4.70 (m, 2H), 3.72 (s, 3H), 3.04-3.01 (m, 1H),2.87-2.83 (m, 1H), 2.71-2.65 (m, 1H), 2.27-2.18 (m, 1H). LC-MS (ESI⁺):m/z 445.1 (M+H)⁺.

Step 3—3-(7-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)piperidine-2,6-dione

To a solution of3-(7-bromo-2-oxobenzo[d]oxazol-3(2H)-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(80 mg, 0.180 mmol) in CH₃CN (2 mL) was added a solution of CAN (690 mg,1.26 mmol) in 0.5 mL of water dropwise at r.t. The reaction mixture wasstirred at r.t. for 2 hours. The reaction mixture was then extractedwith EtOAc (15 mL×2), the organic layer washed with brine, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure. The residuewas purified via Pre-TLC (Petroleum ether/EtOAc=1/1) to give the titlecompound (9.7 mg, 17% yield) as a pale yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.26 (s, 1H), 7.39 (dd, J=8.2, 0.8 Hz, 1H), 7.33-7.27 (m,1H), 7.19 (t, J=8.1 Hz, 1H), 5.42-5.38 (m, 1H), 2.97-2.79 (m, 1H),2.75-2.60 (m, 2H), 2.27-2.12 (m, 1H). LC-MS (ESI⁺): m/z 325.1 (M+H)⁺.

3-[7-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate JG)

Step 1—Tert-ButylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate

To a solution of3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (220 mg, 676umol, Intermediate JF) and tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (411 mg, 1.69 mmol,synthesized via Step 1 of Intermediate CQ) in DMF (10 mL) was added TEA(1.23 g, 12.1 mmol, 1.70 mL), CuI (64.4 mg, 338 umol) and Pd(PPh₃)₂Cl₂(237 mg, 338 umol). The reaction mixture was stirred at 80° C. for 1.5hours under N₂. On completion, the mixture was filtered; and thefiltrate was concentrated in vacuo to give a residue. The residue wasdissolved in DCM (20 mL) and thiourea (resin) (300 mg) was added. Themixture was stirred at 20° C. for 2 hours. Then the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was purified by column chromatography to give the titlecompound (250 mg, 76% yield) as a yellow solid. LC-MS (ESI⁺) m/z 510.2(M+Na)⁺.

Step 2—Tert-ButylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate(250 mg, 512 umol) in THF (10 mL) was added PtO₂ (58.2 mg, 256 umol).The reaction mixture was stirred at 20° C. under H₂ (15 psi) for 1 hour.On completion, the residue was filtered and the filtrate wasconcentrated in vacuo to give the title compound (250 mg, 99%) as yellowoil. LC-MS (ESI⁺) m/z 514.2 (M+Na)⁺.

Step3—3-[7-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]ethoxy]ethyl]carbamate (250 mg, 508 umol) in DCM (4 mL) was addedHCl/dioxane (4 M, 4 mL). The reaction mixture was stirred at 25° C. for1 hour. On completion, the mixture was concentrated in vacuo to give thetitle compound (190 mg, 87% yield) as yellow oil. LC-MS (ESI⁺) m/z 392.3(M+H)⁺.

2-(2,6-Dioxo-3-piperidyl)-5-[3-(methylamino)propyl]-1,3-dione(Intermediate JH)

Step 1—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynyl]-N-methyl-carbamate

To a mixture of tert-butyl N-methyl-N-prop-2-ynyl-carbamate (1.00 g,5.93 mmol, Intermediate IY) and5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1.00 g, 2.97mmol, Intermediate GA) in DMF (4 mL) was added CuI (56.4 mg, 296 umol),TEA (5.40 g, 53.3 mmol, 7.43 mL) and Pd(PPh₃)₂Cl₂ (208 mg, 296 umol).The reaction mixture was heated at 80° C. for 0.5 hour under microwave.On completion, the reaction mixture was diluted with water (30 mL) andextracted with EA (3×50 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography to give the title compound(1.20 g, 95% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14(s, 1H), 7.96-7.88 (m, 3H), 5.16 (dd, J=5.6, 12.8 Hz, 1H), 4.33 (s, 2H),3.33 (s, 3H), 2.89-2.83 (m, 1H), 2.64-2.51 (m, 2H), 2.10-2.02 (m, 1H),1.42 (s, 9H).

Step 2—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propyl]-N-methyl-carbamate

To a mixture of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynyl]-N-methyl-carbamate (2.40 g, 5.64 mmol) in MeOH (50 mL) was added Pd/C(500 mg, 10 wt %) and Pd(OH)₂/C (500 mg, 10 wt %). The reaction mixturewas stirred at 20° C. for 1 hour under H₂ (15 Psi) atmosphere. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (2.40 g, 99% yield) as light yellow solid.LC-MS (ESI⁺) m/z 452.3 (M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-5-[3-(methylamino)propyl]isoindoline-1,3-dione

To a mixture of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propyl]-N-methyl-carbamate(2.40 g, 5.59 mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 19.2 mL).The reaction mixture was stirred at 20° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo to give the titlecompound (2.00 g, 97% yield) as light yellow solid. LC-MS (ESI⁺) m/z330.2 (M+H)⁺.

5-(3-Aminopropyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate JI)

Step 1—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynyl]carbamate

To a solution of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1 g, 2.97 mmol Intermediate GA) and tert-butyl N-prop-2-ynylcarbamate(920 mg, 5.93 mmol) in DMF (4 mL) was added Pd(PPh₃)₂Cl₂ (208 mg, 296umol) TEA (5.40 g, 53 mmol, 7.43 mL) and CuI (57 mg, 296 umol). Themixture was stirred at 80° C. for 0.5 hr under microwave. On completion,the mixture was concentrated in vacuo, the residue was purified bysilica gel chromatography to give the title compound (1.3 g, 95% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 8.01-7.81(m, 3H), 5.17 (dd, J=5.2, 12.8 Hz, 1H), 4.10-4.03 (m, 2H), 3.33 (s, 1H),2.94-2.84 (m, 1H), 2.73-2.53 (m, 2H), 2.13-2.02 (m, 1H), 1.47-1.36 (m,9H); LC-MS (ESI⁺) m/z 434.0 (M+Na)⁺.

Step 2—Tert-ButylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propyl]carbamate

A mixture of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynyl]carbamate(2.5 g, 6.08 mmol), Pd/C (400 mg), Pd(OH)₂/C (400 mg) in THF (40 mL) wasdegassed and purged with H₂ gas 3 times. The mixture was then stirred at20° C. for 16 hrs under H₂ atmosphere at 15 psi. On completion, themixture was filtered and the filtrate was concentrated in vacuo to givethe title compound (2.4 g, 95% yield) as brown solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.12 (s, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.80 (s, 1H), 7.72(dd, J=1.2, 7.6 Hz, 1H), 6.94-6.85 (m, 1H), 5.14 (dd, J=5.2, 12.8 Hz,1H), 2.99-2.84 (m, 3H), 2.82-2.72 (m, 2H), 2.65-2.54 (m, 2H), 2.11-2.01(m, 1H), 1.80-1.68 (m, 2H), 1.38 (s, 9H) LC-MS (ESI⁺) m/z 438.1 (M+Na)⁺.

Step 3—5-(3-Aminopropyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propyl]carbamate(2.4 g, 5.78 mmol) in DCM (25 mL) was added HCl/dioxane (4 M, 10 mL).The mixture was stirred at 20° C. for 2 hrs. On completion, the mixturewas concentrated in vacuo to give the title compound (1.2 g, 65% yield)as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 8.01(s, 3H), 7.88 (d, J=7.6 Hz, 1H), 7.84 (s, 1H), 7.76 (d, J=8.0 Hz, 1H),5.15 (dd, J=5.2, 12.8 Hz, 1H), 2.95-2.84 (m, 3H), 2.83-2.72 (m, 2H),2.69-2.52 (m, 2H), 2.11-2.01 (m, 1H), 1.97-1.89 (m, 2H); LC-MS (ESI⁺)m/z 316.2 (M+H)⁺.

5-(Aminomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate JJ)

Step 1—2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindoline-5-carbonitrile

To a solution of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(450 mg, 1.33 mmol, Intermediate GA), Zn(CN)₂ (94.0 mg, 800 umol) in DMF(15.0 mL) was added Pd(PPh₃)₄ (154 mg, 133 umol). The mixture wasstirred at 100° C. for 3 hours under N₂. On completion, the mixture wasdiluted with H₂O (50 mL), filtered and the solid was dried in vacuo. Thesolid was triturated with PE:EA=5:1 (30 mL), filtered and the solid wasdried in vacuo to give the title compound (200 mg, 52% yield) as purplesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.16 (s, 1H), 8.49 (s, 1H), 8.38(dd, J=1.2, 7.6 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 5.26-5.17 (m, 1H),2.97-2.89 (m, 1H), 2.65-2.58 (m, 1H), 2.57-2.52 (m, 1H), 2.12-2.05 (m,1H).

Step 2—Tert-ButylN-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]methyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindoline-5-carbonitrile (200 mg,706 umol) in THF (10.0 mL) and DMF (10.0 mL) was added (Boc)₂O (169 mg,776 umol) and Raney-Ni (50.0 mg, 583 umol). The mixture was stirred at30° C. for 3 hours under H₂ (50 psi). On completion, the mixture wasfiltered and concentrated in vacuo. The mixture was purified by silicagel column (PE:EA=1:1) to give the title compound (250 mg, 91% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.88 (d, J=7.6Hz, 1H), 7.76 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.63-7.55 (m, 1H),5.18-5.04 (m, 1H), 4.33-4.24 (m, 2H), 2.95-2.88 (m, 1H), 2.84-2.83 (m,1H), 2.64-2.57 (m, 1H), 2.57-2.52 (m, 1H), 2.11-2.01 (m, 1H), 1.39 (s,9H).

Step 3—5-(Aminomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]methyl]carbamate(250 mg, 645 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 4.00mL), and the mixture was stirred at 15° C. for 0.5 hr. On completion,the mixture was concentrated in vacuo to give the title compound (200mg, 90% yield, HCl) as white solid. LC-MS (ESI⁺) m/z 288.1 (M+H)⁺.

2-(2,6-Dioxo-3-piperidyl)-5-[3-[2-(methylamino)ethoxy]propyl]isoindoline-1,3-dione(Intermediate JK)

Step 1—Tert-ButylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynoxy]ethyl]-N-methyl-carbamate

To a solution of tert-butyl N-methyl-N-(2-prop-2-ynoxyethyl)carbamate(2.53 g, 11.8 mmol, Intermediate GK) and5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (2.00 g, 5.93mmol, Intermediate GA) in DMF (4.00 mL) was added TEA (10.8 g, 106mmol), CuI (112 mg, 593 umol) and Pd(PPh₃)₂Cl₂ (416 mg, 593 umol), andthe reaction mixture was heated at 80° C. for 30 min under microwave. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by silica gel column (PE:EA=1:1) to give the title compound(2.7 g, 96% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s,1H), 7.93 (s, 1H), 7.89-7.79 (m, 2H), 5.02-4.96 (m, 1H), 4.44 (s, 2H),3.73 (s, 2H), 3.48 (s, 2H), 2.97 (s, 3H), 2.96-2.91 (m, 1H), 2.89-2.82(m, 1H), 2.82-2.73 (m, 1H), 2.22-2.15 (m, 1H), 1.48 (s, 9H).

Step 2—Tert-ButylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propoxy]ethyl]-N-methyl-carbamate

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynoxy]ethyl]-N-methylcarbamate (2.70 g, 5.75 mmol) in THF (30.0 mL) was addedPd/C (400 mg) and Pd(OH)₂/C (400 mg), and the mixture was stirred at 15°C. for 16 hr under H₂ (15 psi). On completion, the mixture wasconcentrated in vacuo to give the title compound (2.70 g, 95% yield) asblack solid. LC-MS (ESI⁺) m/z 496.1 (M+Na)⁺.

Step3—2-(2,6-Dioxo-3-piperidyl)-5-[3-[2-(methylamino)ethoxy]propyl]isoindoline-1,3-dione

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propoxy]ethyl]-N-methyl-carbamate (2.70 g, 5.70 mmol) in DCM (20.0 mL) was addedHCl/dioxane (4.00 M, 20.0 mL). The mixture was stirred at 15° C. for 0.5hr. On completion, the mixture was concentrated in vacuo to give thetitle compound (2.37 g, 90% yield, HCl) as yellow solid, ¹H NMR (400MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.02 (s, 1H), 7.87-7.74 (m, 3H),5.19-5.10 (m, 1H), 3.67-3.63 (m, 2H), 3.57 (s, 3H), 3.46-3.42 (m, 2H),3.12-3.03 (m, 2H), 2.91-2.86 (m, 2H), 2.64-2.58 (m, 1H), 2.57-2.55 (m,1H), 2.55-2.54 (m, 1H), 2.10-2.01 (m, 1H), 1.94-1.83 (m, 2H).

4-[3-(Difluoromethyl)-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid (Intermediate JL)

Step1—Difluoromethyl)-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

A mixture of methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate(900 mg, 3.37 mmol, Intermediate FW), 2-(4-pyridyl)oxazole-4-carboxylicacid (640 mg, 3.37 mmol, Intermediate ED), DIPEA (1.31 g, 10 mmol, 1.76mL), and HATU (1.54 g, 4.04 mmol) in DMF (20 mL) was degassed and purgedwith N₂ gas 3 times, and then the mixture was stirred at 20° C. for 1 hrunder N₂ atmosphere. On completion, the mixture was concentrated invacuo. The residue was purified by prep-HPLC (basic condition) to givethe title compound (1.45 g, 67% yield) as white solid. LC-MS (ESI⁺) m/z440.2 (M+1)⁺.

Step2—4-[3-(Difluoromethyl)-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid

To a solution of methyl4-[3-(difluoromethyl)-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate (1.60 g, 3.64 mmol) in a mixed of THF (160 mL), MeOH (20 mL)and H₂O (30 mL) was added LiOH (436 mg, 18.2 mmol). The mixture wasstirred at 20° C. for 16 hrs. On completion, the mixture was adjusted topH=6 with 1N HCl, and then filtered and the filter cake was dried invacuo to give the title compound (1.5 g, 96% yield) as white solid.LC-MS (ESI⁺) m/z 426.1 (M+1)⁺.

N-[3-(difluoromethyl)-1-[4-[methyl(2-oxoethyl)carbamoyl]phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide (Intermediate JM)

Step1—N-[3-(difluoromethyl)-1-[4-[2-hydroxyethyl(methyl)carbamoyl]phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

A mixture of4-[3-(difluoromethyl)-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicacid (500 mg, 1.18 mmol, Intermediate JL), 2-(methylamino)ethanol (88.3mg, 1.18 mmol, CAS #109-83-1), DIPEA (456 mg, 3.53 mmol, 614 uL), andHATU (537 mg, 1.41 mmol) in DMF (20 mL) was degassed and purged with N₂gas 3 times, and then the mixture was stirred at 25° C. for 3 hrs underN₂ atmosphere. On completion, the mixture was concentrated in vacuo. Theresidue was purified by prep-HPLC (acid condition) to give the titlecompound (500 mg, 85% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.16 (s, 1H), 9.07 (s, 1H), 8.91-8.74 (m, 3H), 8.03-7.84 (m,4H), 7.59 (d, J=8.4 Hz, 2H), 7.48-7.10 (m, 1H), 4.83 (s, 1H), 3.64-3.38(m, 4H), 3.00 (s, 3H); LC-MS (ESI⁺) m/z 483.2 (M+1)⁺.

Step2—N-[3-(difluoromethyl)-1-[4-[methyl(2-oxoethyl)carbamoyl]phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide

To a solution ofN-[3-(difluoromethyl)-1-[4-[2-hydroxyethyl(methyl)carbamoyl]phenyl]pyrazol-4-yl]-2-(4-pyridyl)oxazole-4-carboxamide(500 mg, 1.04 mmol) in THF (10 mL) was added Dess-Martin (528 mg, 1.24mmol). The mixture was stirred at 25° C. for 3 hrs. On completion, themixture was quenched with saturated Na₂S₂O₃ (10 mL), then extracted withDCM (2×150 mL). The organic layer was concentrated in vacuo to give thetitle compound (490 mg, 98% yield) as yellow solid. LC-MS (ESI⁺) m/z481.2 (M+1)⁺.

2-(2,6-Dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethyl]isoindoline-1,3-dione(Intermediate JN)

Step1—2-(2,6-Dioxo-3-piperidyl)-5-[(E)-2-(2-hydroxyethoxy)vinyl]isoindoline-1,3-dione

To a solution of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(2.00 g, 5.93 mmol Intermediate GA), 2-vinyloxyethanol (1.05 g, 11.8mmol) in dioxane (15.0 mL) was added P(t-Bu)₃ (2.40 g, 1.19 mmol, 10 wt%), Pd₂(dba)₃ (543 mg, 593 umol) andN-cyclohexyl-N-methyl-cyclohexanamine (1.51 g, 7.71 mmol), and themixture was stirred at 25° C. for 16 hrs. On completion, the mixture wasconcentrated in vacuo. The mixture was purified by silica gel column(EA) to give the title compound (2.00 g, 97% yield) as yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.91 (s, 1H), 7.79-7.76 (m, 1H),7.72 (s, 1), 7.71-7.67 (m, 1), 6.08 (d, J=12.8 Hz, 1), 5.17-5.10 (m, 1),4.91-4.86 (m, 1H), 3.96 (t, J=4.8 Hz, 2H), 3.70-3.63 (m, 2H), 2.95-2.84(m, 1H), 2.65-2.57 (m, 1H), 2.57-2.53 (m, 1), 2.11-2.01 (m, 1H).

Step2—2-(2,6-Dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethyl]isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-5-[(E)-2-(2-hydroxyethoxy)vinyl]isoindoline-1,3-dione(1.00 g, 2.90 mmol) in THF (40.0 mL) was added Pd/C (300 mg, 10 wt %)and Pd(OH)₂/C (300 mg, 10 wt %). The mixture was stirred at 15° C. for12 hours under H₂ (15 psi). On completion, the mixture was filtered andconcentrated in vacuo to give the title compound (1.00 g, 95% yield) asyellow solid. LC-MS (ESI⁺) m/z 347.2 (M+H)⁺.

2-[2-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]ethoxy]ethylmethanesulfonate (Intermediate JO)

To a solution of2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethyl]isoindoline-1,3-dione(300 mg, 866 umol, Intermediate JN) in DCM (30.0 mL) was added MsCl (148mg, 1.30 mmol) and TEA (262 mg, 2.60 mmol), and the mixture was stirredat 15° C. for 0.5 hr. On completion, the mixture was diluted with DCM(20 mL), and extracted with H₂O (3×20 mL). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (350 mg, 95% yield) as yellow oil. LC-MS (ESI⁺) m/z 425.2(M+H)⁺.

4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine (Intermediate JP)

Step 1—Tert-butyl4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate(3.43 g, 12.26 mmol, synthesized via Step 1 of Intermediate CX) and3-(difluoromethyl)-4-nitro-1H-pyrazole (2 g, 12.26 mmol, IntermediateHS) in DMF (20 mL) was added Cs₂CO₃ (7.99 g, 24.5 mmol). The reactionmixture was stirred at 115° C. for 12 hours. On completion, the mixturewas filtered, and the filtrate was concentrated in vacuo. The residuewas purified by silica column chromatography (PE/EA, 5/1 to 1/1) to givethe title compound (2.00 g, 44.1% yield) as a yellow solid. LC-MS (ESI⁺)m/z 291.0 (M+H−56)⁺.

Step 2—4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine

To a solution of tert-butyl4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine-1-carboxylate (1g, 2.89 mmol) in DCM (10 mL) was added HCl (4 M, 20 mL). The reactionmixture was concentrated in vacuo to give the title compound (830 mg,HCl, 85% purity) as a white solid. LC-MS (ESI⁺) m/z 247.0 (M+H)⁺.

5-[2-[2-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate JO)

Step1—5-[2-[2-[4-[3-(Difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]ethoxy]ethylmethanesulfonate (225 mg, 530 umol, Intermediate JO),4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine (100 mg, 353 umol,HCl, Intermediate JP) in ACN (2.00 mL) was added KI (5.87 mg, 35.3 umol)and NaHCO₃ (89.1 mg, 1.06 mmol). The mixture was stirred at 80° C. for16 hrs. On completion, the mixture was concentrated in vacuo. Themixture was purified by silica gel column (DCM:MeOH=50:1) to give thetitle compound (100 mg, 49% yield) as white solid. LC-MS (ESI⁺) m/z575.1 (M+H)⁺.

Step2—5-[2-[2-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of5-[2-[2-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(90.0 mg, 156 umol) in THF (5.00 mL) was added PtO₂ (3.56 mg, 15.6umol), the mixture was stirred at 15° C. for 16 hrs under H₂ (15 psi).On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (85.0 mg, 90% yield) asyellow solid. LC-MS (ESI⁺) m/z 545.3 (M+H)⁺.

5-[3-(2-Aminoethoxy)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate JR)

Step 1—Tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynoxy]ethyl]carbamate

To a solution of tert-butyl N-(2-prop-2-ynoxyethyl)carbamate (2.36 g,11.8 mmol synthesized via Step 1 on Intermediate CP),5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (2.00 g, 5.93mmol, Intermediate GA) in DMF (4.00 mL) was added CuI (112 mg, 593umol), Pd(PPh₃)₂Cl₂ (416 mg, 593 umol), and TEA (10.8 g, 106 mmol). Themixture was stirred at 80° C. for 0.5 hr. On completion, the mixture wasconcentrated in vacuo. The mixture was purified by silica gel column(PE:EA=1:1) to give the title compound (2.60 g, 96% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.2 (s, 1H), 8.01 (s, 1H), 8.00 (s,2H), 6.97-6.87 (m, 1H), 5.28-5.17 (m, 1H), 4.52 (s, 2H), 3.66-3.55 (m,2H), 3.25-3.17 (m, 2H), 2.95-2.89 (m, 1), 2.71-2.63 (m, 1), 2.62-2.58(m, 1), 2.17-2.09 (m, 1), 1.43 (s, 9H).

Step 2—Tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]prop-2-ynoxy]ethyl]carbamate (2.60 g, 5.71 mmol) in THF (30.0 mL) was added Pd/C (500mg, 10 wt %), and Pd(OH)₂/C (500 mg, 10 wt %). The mixture was stirredat 15° C. for 16 hours under H₂ (15 psi). On completion, the mixture wasfiltered and concentrated in vacuo to give the title compound (2.40 g,91% yield) as yellow solid. LC-MS (ESI⁺) m/z 482.3 (M+Na)⁺.

Step3—5-[3-(2-Aminoethoxy)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propoxy]ethyl]carbamate (2.40 g, 5.22 mmol) in DCM (15.0 mL) was added HCl/dioxane(4.00 M, 15.0 mL). The mixture was stirred at 15° C. for 0.5 hour. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (2.00 g, 90% yield, HCl) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.18 (s, 1), 8.14 (s, 2H), 7.91 (d, J=7.6 Hz, 1), 7.87 (s,1H), 7.81 (d, J=7.6 Hz, 1H), 5.25-5.15 (m, 1H), 3.66-3.63 (m, 2H),3.52-3.47 (m, 2H), 3.07-2.98 (m, 2H), 2.97-2.94 (m, 1H), 2.93-2.88 (m,2H), 2.70-2.64 (m, 1H), 2.62-2.58 (m, 1H), 2.15-2.08 (m, 1H), 1.99-1.90(m, 2H).

Methyl 4-(3-bromo-4-nitro-pyrazol-1-yl)benzoate (Intermediate JS

To a solution of 3-bromo-4-nitro-1H-pyrazole (4.8 g, 25.0 mmol, CAS#784193-37-9) and (4-methoxycarbonylphenyl) boronic acid (6.75 g, 37.5mmol, CAS #99768-12-4) in DCM (100 mL) was added Cu(OAc)₂ (4.54 g, 25.0mmol), and pyridine (7.91 g, 100 mmol) under O₂ (15 Psi). The reactionmixture was stirred at 20° C. for 12 hours under O₂ (15 Psi) atmosphere.On completion, the mixture was washed with NH₃·H₂O (50 mL), filtered andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with 2 N aq.HCl (60 mL) and brine (2×100 mL), dried overanhydrous sulfate sodium, filtered and concentrated in vacuo. The crudeproduct was triturated with PE:EA=10:1 (100 mL) to give the titlecompound (5.00 g, 61% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.82 (s, 1H), 8.11-8.06 (m, 4H), 3.88 (s, 3H).

Methyl4-[4-amino-3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]pyrazol-1-yl]benzoate(Intermediate JT)

Step 1—Methyl4-[3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]-4-nitro-pyrazol-1-yl]benzoate

A mixture of methyl 4-(3-bromo-4-nitro-pyrazol-1-yl)benzoate (500 mg,1.53 mmol, 1 eq, Intermediate JS), 1-(2-hydroxyethyl)imidazolidin-2-one(239 mg, 1.84 mmol, CAS #3699-54-5), bis (tetrabutylammonium iodide)copper[I] (132 mg, 306 umol), K₂CO₃ (423 mg, 3.07 mmol) andN1,N2-dimethylethane-1,2-diamine (27.0 mg, 306 umol) in dioxane (25 mL)was degassed and purged with N₂ 3 times. Then the mixture was stirred at110° C. for 16 hours under N₂ atmosphere. The mixture was filtered andthe filtrate was concentrated in vacuo. The residue was purified byPre-HPLC(acid condition) give the title compound (110 mg, 17% yield) asyellow solid; LC-MS (ESI⁺) m/z 376.0 (M+H)⁺.

Step 2—Methyl4-[4-amino-3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]pyrazol-1-yl]benzoate

To a solution of methyl4-[3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]-4-nitro-pyrazol-1-yl]benzoate(110 mg, 293 umol) in THF (10 mL) was added Pd/C (20 mg, 10 wt %). Themixture was stirred at 20° C. for 3 hours under H₂ (15 Psi). Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (100 mg, 98% yield) asyellow solid; LC-MS (ESI⁺) m/z 346.2 (M+H)⁺.

3,3-Dimethylpyrrolidin-2-one (Intermediate JU)

Step 1—Tert-butyl 2-oxopyrrolidine-1-carboxylate

To a solution of pyrrolidin-2-one (20 g, 235 mmol) in ACN (450 mL) wasadded (Boc)₂0 (61.5 g, 282 mmol) and DMAP (2.87 g, 23.50 mmol) at 0° C.The mixture was stirred at 10° C. for 16 hours. On completion, themixture was concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, PE/EA=3/1) to give the title compound (38 g, 87%yield) as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 3.74 (t, J=7.2Hz, 2H), 2.50 (t, J=8.2 Hz, 2H), 2.06-1.93 (m, 2H), 1.52 (s, 9H).

Step 2—Tert-Butyl 3,3-dimethyl-2-oxo-pyrrolidine-1-carboxylate

To a mixture of tert-butyl 2-oxopyrrolidine-1-carboxylate (4.5 g, 24.3mmol) in THF (50 mL) was added LiHMDS (1.0 M, 25.5 mL) at −70° C. Thenthe reaction mixture was stirred at −30° C. for 0.5 hour. MeI (8.62 g,60.7 mmol) was added to the mixture. The reaction mixture was stirred at25° C. for 1 hour. On completion, the mixture was concentrated in vacuo.The residue was quenched with water (30 mL) and extracted with EtOAc(3×30 mL). The organic layer was dried with Na₂SO₄, filtrated andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂, PE:EA=5:1) to give the title product (2.80 g, 54% yield) ascolorless solid. ¹H NMR (400 MHz, CDCl₃) δ 3.67 (t, J=7.2 Hz, 2H), 1.85(t, J=7.2 Hz, 2H), 1.55 (s, 9H), 1.20 (s, 6H).

Step 3—3,3-Dimethylpyrrolidin-2-one

To a mixture of tert-butyl 3,3-dimethyl-2-oxo-pyrrolidine-1-carboxylate(2.0 g, 9.38 mmol,) in DCM (3 mL) was added HCl/dioxane (4 M, 2.00 mL).Then the reaction mixture was stirred at 25° C. for 12 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (1.00 g, 94% yield) as yellowish solid. ¹H NMR (400 MHz,DMSO-d₆) δ 3.06 (t, J=6.8 Hz, 2H), 1.76 (t, J=6.8 Hz, 2H), 0.93 (s, 6H).

Methyl4-[4-amino-3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)pyrazol-1-yl]benzoate(Intermediate JV)

Step 1—Methyl4-[3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-4-nitro-pyrazol-1-yl]benzoate

A mixture of methyl 4-(3-bromo-4-nitro-pyrazol-1-yl)benzoate (500 mg,1.53 mmol, Intermediate JS), 3,3-dimethylpyrrolidin-2-one (208 mg, 1.84mmol, Intermediate JU), bis(tetrabutylammonium iodide) copper[I] (132mg, 306 umol), K₂CO₃ (423 mg, 3.07 mmol) andN,N′-dimethylethane-1,2-diamine (27.0 mg, 306 umol) in dioxane (20 mL)was degassed and purged with N₂ gas 3 times, and then the mixture wasstirred at 110° C. for 16 hours under N₂ atmosphere. On completion, thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by Pre-HPLC (acid condition) to give thetitle compound (200 mg, 18% yield) as yellow solid, LC-MS (ESI⁺) m/z359.2 (M+H)⁺.

Step 2—Methyl4-[4-amino-3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)pyrazol-1-yl]benzoate

To a solution of methyl4-[3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-4-nitro-pyrazol-1-yl]benzoate(50 mg, 139 umol) in MeOH (5 mL) was added Pd/C (30 mg, 10 wt %) underN₂. The suspension was degassed under vacuum and purged with H₂ gasthree times. The mixture was stirred at 20° C. for 3 hours under H₂ (15Psi). On completion, the reaction mixture was concentrated in vacuo togive the title compound (45 mg, 97% yield) as light yellow solid; LC-MS(ESI⁺) m/z 329.2 (M+H)⁺.

2-(2,6-Dioxo-3-piperidyl)-4-(4-piperidylamino)isoindoline-1,3-dione(Intermediate JW)

Step 1—Tert-Butyl4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]piperidine-1-carboxylate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (2.5 g, 9.05mmol, Intermediate R) and tert-butyl 4-aminopiperidine-1-carboxylate(1.81 g, 9.05 mmol, CAS #502482-34-0) in dioxane (25 mL) was added DIPEA(4.68 g, 36.2 mmol). The reaction mixture was stirred at 115° C. for 15hrs. On completion, the mixture was concentrated in vacuo. The residuewas purified by silica gel chromatography to give the title compound(2.16 g, 52% yield) as a yellow solid. LC-MS (ESI⁺) m/z 479.1 (M+Na)⁺.

Step2—2-(2,6-Dioxo-3-piperidyl)-4-(4-piperidylamino)isoindoline-1,3-dione

To a solution of tert-butyl4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]piperidine-1-carboxylate(2.16 g, 4.73 mmol) in DCM (5 mL) was added HCl/dioxane (10 mL). Thereaction mixture was stirred at 20° C. for 2 hrs. On completion, themixture was concentrated in vacuo. The residue was triturated with DCM(50 mL), stirred and filtered. The filter cake was dried in vacuo togive the title compound (1.20 g, 65% yield, HCl) as a yellow greensolid. LC-MS (ESI⁺) m/z 357.1 (M+H)⁺.

Tert-Butyl N-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy]ethyl]carbamate(Intermediate JX)

To a solution of DMSO (1.33 g, 17.0 mmol) in DCM (10 mL) was added asolution of (COCl)₂ (1.73 g, 13.6 mmol) in DCM (15 mL) dropwise at −70°C. The mixture was stirred at this temperature for 10 minutes. Then asolution of tert-butylN-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (2.00 g, 6.82mmol, synthesized via Steps 1-3 of Intermediate AO) in DCM (15 mL) wasadded into the above mixture slowly. After stirred at −70° C. for 50minutes, TEA (5.52 g, 54.5 mmol) was added and the reaction mixture wasstirred at −70° C. for 0.5 hr. On completion, the mixture was quenchedwith water (30 mL), and then separated. The aqueous phase was extractedwith DCM (2×30 mL). Then the organic phase was combined and washed withbrine (2×30 mL), dried over Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to give the title compound (1.50 g, 76% yield) asyellow oil, which was used directly in the next step without furtherpurification.

4-[[1-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate JY)

Step 1—Tert-ButylN-[2-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (386 mg, 1.32mmol, Intermediate JX) and2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylamino)isoindoline-1,3-dione (400mg, 1.02 mmol, HCl, Intermediate JW) in THF (20 mL) was added KOAc (200mg, 2.04 mmol). One hour later, NaBH(OAc)₃ (432 mg, 2.04 mmol) was addedand the reaction mixture was stirred at 20° C. for 16 hrs. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by reverse phase (0.1% HCl condition) to give the titlecompound (550 mg, 86% yield) as a yellow solid. LC-MS (ESI⁺) m/z 632.4(M+H)⁺

Step2—4-[[1-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3—piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (550 mg, 871umol) in DCM (5 mL) was added HCl/dioxane (10 mL). The reaction mixturewas stirred at 20° C. for 10 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (460 mg, 93% yield,HCl) as a yellow solid. LC-MS (ESI⁺) m/z 532.2 (M+H)⁺.

5-[[1-[2-(2-Aminoethoxy)ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate JZ)

Step 1—Tert-butylN-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]-1-piperidyl]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(4-piperidylamino)isoindoline-1,3-dione (400mg, 1.02 mmol, HCl, synthesized via Steps 1-2 of Intermediate HZ),tert-butyl N-[2-(2-oxoethoxy)ethyl]carbamate (310 mg, 1.53 mmol,synthesized via Step 1 of Intermediate FS) in a mixed solvent of THF(10.0 mL) and DCM (10.0 mL) was added KOAc (199 mg, 2.04 mmol), themixture was stirred at 15° C. for 0.5 hr, then NaBH(OAc)₃ (431 mg, 2.04mmol) was added, and the mixture was stirred at 15° C. for 16 hrs. Oncompletion, the mixture was quenched with H₂O (2.00 mL) and concentratedin vacuo. The crude product was purified by reverse phase: (0.1% HClcondition) to give the title compound (380 mg, 68% yield) as yellowsolid. LC-MS (ESI⁺) m/z 544.4 (M+H)⁺.

Step2—5-[[1-[2-(2-Aminoethoxy)ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]-1-piperidyl]ethoxy]ethyl]carbamate (380 mg, 699 umol) in DCM(3.00 mL) was added HCl/dioxane (4.00 M, 5.00 mL), the mixture wasstirred at 15° C. for 0.5 hr. On completion, the mixture wasconcentrated in vacuo to give the title compound (300 mg, 90% yield,HCl) as yellow solid. LC-MS (ESI⁺) m/z 444.1 (M+H)⁺.

5-[[1-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate KA)

Step 1—Tert-butylN-[2-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(4-piperidylamino)isoindoline-1,3-dione (400mg, 1.02 mmol, HCl, synthesized via Steps 1-2 of Intermediate HZ) in THF(20 mL) was added TEA (206 mg, 2.04 mmol, 283 uL). The mixture wasstirred at 20° C. for 30 minutes, then tert-butylN-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy] ethyl]carbamate (385 mg, 1.32mmol, Intermediate JX), HOAc (183 mg, 3.05 mmol, 174 uL) and NaBH(OAc)₃(431 mg, 2.04 mmol) was added to the mixture. The reaction mixture wasstirred at 20° C. for 16 hours. On completion, the mixture was filtered,and the filtrate was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (400 mg, 62% yield) as a yellow solid. LC-MS (ESI⁺) m/z632.4 (M+H)⁺.

Step2—5-[[1-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3—piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (400 mg, 633umol) in DCM (5 mL) was added HCl/dioxane (4 M, 6.20 mL). The reactionmixture was stirred at 25° C. for 1 hour. On completion, the mixture wasconcentrated in vacuo to give the title compound (350 mg, 97% yield) asa yellow solid. LC-MS (ESI⁺) m/z 532.4 (M+H)⁺.

4-[4-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate KB)

Step 1—Tert-ButylN-[2-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of2-(2,6-dioxo-3-piperidyl)-4-piperazin-1-yl-isoindoline-1,3-dione (250mg, 659 umol, HCl, synthesized via Steps 1-2 Intermediate IA) and TEA(66.7 mg, 659 umol, 91.8 uL) in THF (10 mL) and DMF (5 mL) was addedtert-butyl N-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (249mg, 857 umol, Intermediate JX), HOAc (39.6 mg, 659 umol, 37.7 uL) andNaBH(OAc)₃ (279 mg, 1.32 mmol). The reaction mixture was stirred at 20°C. for 20 hours. On completion, the reaction mixture was concentrated invacuo. The residue was purified by prep-HPLC (FA condition) to give thetitle compound (200 mg, 49% yield) as yellow solid. LC-MS (ESI⁺) m/z618.4 (M+H)⁺.

Step2—4-[4-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[2-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 323 umol)in DCM (5 mL) was added HCl/dioxane (4 M, 10 mL). The reaction mixturewas stirred at 20° C. for 3 hours. On completion, the reaction mixturewas concentrated in vacuo to give the title compound (179 mg, 99% yield,HCl) light yellow gum. LC-MS (ESI⁺) m/z 518.3 (M+H)⁺.

3-(5-Bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (Intermediate KC)

Step 1—Methyl 4-bromo-2-(bromomethyl)benzoate

To a solution of methyl 4-bromo-2-methyl-benzoate (5.00 g, 21.8 mmol,CAS #99548-55-7) in CCl₄ (50.0 mL), NBS (4.66 g, 26.1 mmol) and AIBN(358 mg, 2.18 mmol) were added. The reaction mixture was stirred at 80°C. for 24 hrs. On completion, the reaction was filtered and concentratedin vacuo. The residue was purified by silica gel chromatography(PE:EA=20:1) to give the title compound (5.1 g, 76% yield) as colorlessliquid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (d, J=8.4 Hz, 1H), 7.59 (s,1H), 7.54-7.52 (m, 1H), 4.92 (s, 2H), 3.96 (s, 3H).

Step 2—3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione

To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.1 mmol, HCl)and methyl 4-bromo-2-(bromomethyl)benzoate (5.10 g, 16.5 mmol) in DMF(50.0 mL) was added TEA (4.92 g, 48.6 mmol). The reaction mixture wasstirred at 75° C. for 12 hrs. On completion, the reaction mixture wasdiluted with water (200 mL) and filtered. The filtered cake wascollected. The reaction mixture was concentrated in vacuo. The residuewas triturated with EA:H₂O=1:1 (50 mL) to give the title compound (1.70g, 39% yield) as blue solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H),7.90 (s, 1H), 7.74-7.66 (m, 2H), 5.14-5.09 (m, 1H), 4.50-4.33 (m, 2H),2.95-2.86 (m, 1H), 2.70-2.61 (m, 1H), 2.42-2.36 (m, 1H), 2.04-2.01 (m,1H).

3-(1-Oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione(Intermediate KD)

Step 1—Tert-Butyl4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate

To a solution of 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione(500 mg, 1.55 mmol, Intermediate KC), and tert-butylpiperazine-1-carboxylate (413 mg, 1.86 mmol, HCl) in dioxane (40.0 mL)was added Cs₂CO₃ (1.01 g, 3.09 mmol), RuPhos (144 mg, 309 umol),[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (240 mg, 309umol) and 4A molecular sieves (30.0 mg), and the mixture was stirred at100° C. for 16 hr under N₂. On completion, the mixture was filtered andthe filtrate was concentrated in vacuo. The mixture was purified byreverse phase: (0.1% HCl) to give the title compound (350 mg, 95% yield)as yellow oil, LC-MS (ESI⁺) m/z 429.3 (M+H)⁺.

Step 2—3-(1-Oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione

To a solution of tert-butyl4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazine-1-carboxylate(160 mg, 373 umol) in DCM (2.00 mL) was added HCl/dioxane (4.00 M, 4.00mL), the mixture was stirred at 15° C. for 0.5 hr. On completion, themixture was concentrated in vacuo to give the title compound (130 mg,90% yield, HCl) as yellow solid. LC-MS (ESI⁺) m/z 329.2 (M+H)⁺.

3-[5-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(Intermediate KE)

Step 1—Tert-ButylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of3-(1-oxo-5-piperazin-1-yl-isoindolin-2-yl)piperidine-2,6-dione (130 mg,356 umol, HCl, Intermediate KE), tert-butylN-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (105 mg, 427 umol,Intermediate HY) in THF (10.0 mL) was added KOAc (69.9 mg, 712 umol).The mixture was stirred at 15° C. for 0.5 hr, then NaBH(OAc)₃ (151 mg,712 umol) was added, and the mixture was stirred at 15° C. for 16 hrs.On completion, the mixture was diluted with H₂O (1.00 mL) andconcentrated in vacuo. The crude product was purified by reverse phase:(0.1% HCl) to give the title compound (130 mg, 65% yield) as yellowsolid. LC-MS (ESI⁺) m/z 560.4 (M+H)⁺

Step2—3-[5-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate(130 mg, 232 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 4.00mL), and the mixture was stirred at 15° C. for 0.5 hr. On completion,the mixture was concentrated in vacuo to give the title compound (110mg, 90% yield, HCl) as yellow solid. LC-MS (ESI⁺) m/z 460.4 (M+H)⁺.

5-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate KF)

Step 1—Tert-ButylN-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (500mg, 1.32 mmol, HCl, synthesized via Steps 1-2 of Intermediate IB) in amixed solvent of DCM (20 mL) and DMF (6 mL) was added TEA (200 mg, 1.98mmol), HOAc (158 mg, 2.64 mmol) and tert-butylN-[2-(2-oxoethoxy)ethyl]carbamate (804 mg, 3.96 mmol, synthesized viaStep 1 of Intermediate FS) at 5° C. The mixture was stirred at 5° C. for30 minutes, and then NaBH(OAc)₃ (559 mg, 2.64 mmol) was added at 0° C.,the mixture was stirred at 10° C. for 72 hours. On completion, thereaction mixture was quenched by water (0.1 mL), and then concentratedin vacuo. The residue was purified by prep-HPLC (FA condition) to givethe title compound (0.40 g, 53% yield) as yellow solid. LC-MS (ESI⁺) m/z530.2 (M+H)⁺.

Step2—5-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethyl]carbamate(0.37 g, 649 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 3 mL). Themixture was stirred at rt for 1.5 hours. On completion, the reactionmixture was concentrated in vacuo to give the title compound (0.28 g,91% yield, HCl) as yellow solid. LC-MS (ESI⁺) m/z 430.1 (M+H)⁺.

2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide(Intermediate KG)

Step 1—Tert-ButylN-[4-[4-[[1-[4-(azidomethyl)phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-1]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a mixture of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(1 g, 1.72 mmol, synthesized via Step 1-2 of Intermediate GF) in THF (20mL) was added DPPA (2.37 g, 8.61 mmol) at 0° C., then DBU (1.31 g, 8.61mmol) was added. The mixture was stirred at 20° C. for 16 hrs. Oncompletion, the mixture was quenched with water (10 mL), then extractedwith EA (2×50 mL). The organic layer was concentrated in vacuo to give aresidue, which was purified by silica gel chromatography to give thetitle compound (700 mg, 67% yield) as white solid. LC-MS (ESI⁺) m/z606.3 (M+1)⁺.

Step 2—Tert-butylN-[4-[4-[[1-[4-(aminomethyl)phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of tert-butylN-[4-[4-[[1-[4-(azidomethyl)phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate (700mg, 1.16 mmol) in THF (100 mL) was added Pd/C (50 mg, 10 wt %). Thesuspension was degassed and purged with H₂ for 3 times. The mixture wasstirred under H₂ (15 Psi) at rt for 16 hrs. On completion, the mixturewas filtered and the filtrate was concentrated in vacuo to give thetitle compound (500 mg, 74% yield) as white solid. LC-MS (ESI⁺) m/z580.3 (M+1)⁺.

Step 3—Tert-Butyl(2S,4R)-2-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate

A mixture of(2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-pyrrolidine-2-carboxylic acid(199 mg, 862 umol, CAS #13726-69-7), tert-butylN-[4-[4-[[1-[4-(aminomethyl)phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(500 mg, 862 umol), HATU (393 mg, 1.04 mmol), and DIPEA (334 mg, 2.59mmol) in DMF (3 mL) was degassed and purged with N₂ gas 3 times, andthen the mixture was stirred at rt for 2 hrs under N₂ atmosphere. Oncompletion, the reaction mixture was quenched with water 20 mL, and thenextracted with EA (2×100 mL). The combined organic layer was washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by prep-HPLC to give the titlecompound (460 mg, 67% yield) as white solid. LC-MS (ESI⁺) m/z 793.2(M+1)⁺.

Step4—2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butyl(2S,4R)-2-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate(200 mg, 252 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 3 mL). Themixture was stirred at rt for 16 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (150 mg, 94% yield) aswhite solid. LC-MS (ESI⁺) m/z 593.4 (M+1)⁺.

N-[1-[4-[[[(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidine-2-carbonyl]amino]methyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide(Intermediate KH)

Step 1—Tert-ButylN-[(1S)-1-[(2S,4R)-2-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]

A mixture of2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide(70 mg, 111 umol, HCl, Intermediate KG),(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (26 mg, 111umol, CAS #62965-35-9), HATU (51 mg, 133 umol), and DIPEA (43. mg, 334umol) in DMF (5 mL) was degassed and purged with N₂ gas 3 times, andthen the mixture was stirred at rt for 2 hrs under N₂ atmosphere. Oncompletion, the mixture was concentrated in vacuo, the residue waspurified by prep-HPLC to give the title compound (65 mg, 65% yield) aswhite solid. LC-MS (ESI⁺) m/z 806.5 (M+1)⁺.

Step2—N-[1-[4-[[[(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-pyrrolidine-2-carbonyl]amino]methyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[(1S)-1-[(2S,4R)-2-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-4-hydroxy-pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]carbamate(100 mg, 124 umol) in DCM (6 mL) was added HCl/dioxane (4 M, 2 mL). Themixture was stirred at rt for 2 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (95 mg, 100% yield) aswhite solid. LC-MS (ESI⁺) m/z 706.2 (M+1)⁺

O1-BenzylO2-[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate(Intermediate KI)

Step 1—O1-benzylO2-[(3R,5S)-1-tert-butoxycarbonyl-5-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate

To a solution of (2S)-1-benzyloxycarbonylpyrrolidine-2-carboxylic acid(72.3 mg, 290 umol) in DCM (10 mL) was added EDCI (83.4 mg, 435 umol)and DMAP (3.54 mg, 29.0 umol) at 0° C., thentert-butyl(2S,4R)-2-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate(230 mg, 290 umol, synthesized via Steps 1-3 of Intermediate KG) wasadded to the mixture, and the reaction mixture was stirred at rt for 12hr. On completion, the mixture was diluted with H₂O (5 mL), thenconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (280 mg,94% yield) as a white solid. LC-MS (ESI⁺) m/z 1024.6 (M+H)⁺.

Step 2—O1-benzylO2-[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate

To a solution of O1-benzyl O2-[(3R,5S)-1-tert-butoxycarbonyl-5-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate (260 mg, 253 umol) in DCM (2 mL) wasadded TFA (1.54 g, 13.5 mmol, 1 mL), and the reaction mixture wasstirred at rt for 12 hr. On completion, the mixture was concentrated invacuo to give the title compound (200 mg, 96% yield) as a white solid.LC-MS (ESI⁺) m/z 824.4 (M+H)⁺.

O2-[(3R,5S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]O1-benzyl (2S)-pyrrolidine-1,2-dicarboxylate (Intermediate KJ)

Step 1—(S)-1-Benzyl2-((3R,5S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-((4-(4-(2-(2-((cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)benzyl)carbamoyl)pyrrolidin-3-yl)pyrrolidine-1,2-dicarboxylate

To a solution of O1-benzylO2-[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate(140 mg, 169 umol, Intermediate KI) and(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (39.3 mg,169 umol, CAS #62965-35-9) in DMF (10 mL) was added DIPEA (21.9 mg, 169umol, 29.6 uL) and HATU (77.5 mg, 203 umol), and the mixture was stirredat rt for 12 hr. On completion, the mixture was quenched by addition ofH₂O (5 mL), and then concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (160 mg, 91% yield) as a white solid. LC-MS (ESI⁺) m/z1037.3 (M+H)⁺.

Step2—O2-[(3R,5S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]O1-benzyl (2S)-pyrrolidine-1,2-dicarboxylate

To a solution of O1-benzylO2-[(3R,5S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate (150 mg, 144 umol) in DCM (4 mL) wasadded TFA (3.08 g, 27.0 mmol, 2.0 mL), and the reaction mixture wasstirred at rt for 3 hr. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (130 mg, 96% yield) asa yellow solid. LC-MS (ESI⁺) m/z 937.5 (M+H)⁺.

4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate KK)

Step1—Tert-butylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethyl]carbamate

To a mixture of2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylamino)isoindoline-1,3-dione (200mg, 509 umol, HCl, Intermediate JW) in DCM (10 mL) was added KOAc (99.9mg, 1.02 mmol) and stirred at 1 hr. Tert-butylN-[2-[2-(3-oxopropoxy)ethoxy]ethyl]carbamate (133 mg, 509 umol,Intermediate HY) and NaBH(OAc)₃ (216 mg, 1.02 mmol) was added into themixture. The reaction mixture was stirred at rt for 11 hrs. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA) to give the title compound (165 mg,55% yield) as a yellow solid. LC-MS (ESI⁺) m/z 588.2 (M+H)⁺.

Step2—4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethyl]carbamate(165 mg, 281 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 0.7 mL).The reaction mixture was stirred at rt for 0.5 hr. On completion, themixture was concentrated in vacuo to give the title compound (136 mg,92% yield, HCl) as brown oil. LC-MS (ESI⁺) m/z 488.2 (M+H)⁺.

4-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate KL)

Step 1—Tert-ButylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-piperazin-1-yl-isoindoline-1,3-dione (250mg, 660 umol, HCl, synthesized via Steps 1-2 Intermediate IA) andtert-butyl N-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (212 mg, 858umol, Intermediate HY) in a mixed solvent of THF (15 mL) and DCM (5 mL)was added KOAc (130 mg, 1.32 mmol). Then one hour later, NaBH(OAc)₃ (280mg, 1.32 mmol) was added and the reaction mixture was stirred at rt for17 hrs. On completion, the mixture was concentrated in vacuo. Theresidue was purified by reverse phase (0.1% HCl condition) to give thetitle compound (110 mg, 29% yield) as a yellow solid. LC-MS (ESI⁺) m/z574.2 (M+H)⁺.

Step2—4-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate (110 mg, 192 umol) in DCM(4 mL) was added HCl/dioxane (4 mL). The reaction mixture was stirred atrt for 1 hr. On completion, the mixture was concentrated in vacuo togive the title compound (90 mg, 92% yield, HCl) as a yellow solid. LC-MS(ESI⁺) m/z 474.2 (M+H)⁺.

Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[methyl(2-oxoethyl)carbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(Intermediate KM)

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[2-hydroxyethyl(methyl)carbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (300 mg, 510 umol, Intermediate DF) and 2-(methylamino) ethanol(38.3 mg, 510 umol, 41.0 U1, CAS #109-83-1) in DMF (2 mL) was added HATU(232 mg, 612 umol) and DIPEA (329 mg, 2.55 mmol, 444 uL), and thereaction mixture was stirred at rt for 12 hrs. On completion, themixture was filtered, and the filter cake was dried in vacuo to give thetitle compound (210 mg, 64% yield) as a yellow solid. LC-MS (ESI⁺) m/z645.4 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[methyl(2-oxoethyl)carbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[2-hydroxyethyl(methyl)carbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(160 mg, 248 umol) in THF (5 mL) was added DMP (126 mg, 297 umol, 92.2uL). The reaction mixture was stirred at rt for 2 hours. On completion,the mixture was diluted with H₂O (20 mL), then extracted with DCM (2×30mL). The combined organic layer was then washed with Na₂S₂O₃ (30 mL),NaHCO₃ (30 mL), and concentrated in vacuo to give the title compound(150 mg, 94% yield) as a yellow solid. LC-MS (ESI⁺) m/z 643.4 (M+H)⁺.

Tert-Butyl N-[2-[3-(2-aminoethoxy)propoxy]ethyl]carbamate (IntermediateKN)

Step 1—Ethyl 2-[3-(2-ethoxy-2-oxo-ethoxy)propoxy]acetate

To a solution of propane-1,3-diol (15.0 g, 197 mmol, CAS #126-30-7) andRh(OAc)₂ (435 mg, 1.97 mmol) in DCM (200 mL) was added a solution ofethyl 2-diazoacetate (67.4 g, 591 mmol) in DCM (100 mL) dropwise. Themixture was stirred at 10° C. for 16 hours. On completion, the mixturewas diluted with H₂O (150 mL) and extracted with DCM (3×150 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂) to give the title compound (30.0 g, 61%yield) as colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ 4.21 (q, J=7.2 Hz,4H), 4.07 (s, 4H), 3.65 (t, J=6.4 Hz, 4H), 1.99-1.89 (m, 2H), 1.28 (t,J=7.2 Hz, 6H).

Step 2—2-[3-(2-Hydroxyethoxy)propoxy]ethanol

To a solution of ethyl 2-[3-(2-ethoxy-2-oxo-ethoxy)propoxy]acetate (20.0g, 80.5 mmol) in THF (300 mL) was added LiAlH₄ (6.24 g, 161 mmol, 98%purity) at 0° C. The mixture was then stirred at 10° C. for 1 hour. Oncompletion, the mixture was quenched with water (10 mL) and NaOH aqueussolution (15%, 10 mL) at 0° C., and the reaction was filtered. Thefiltrate was dried over Na₂SO₄, filtered and concentrated in vacuo togive the title compound (12 g, 90% yield) as colourless oil. ¹H NMR (400MHz, DMSO-d₆) δ 4.53 (t, J=5.2 Hz, 2H), 3.50-3.45 (m, 4H), 3.43 (t,J=6.4 Hz, 4H), 3.37 (t, J=5.2 Hz 4H), 1.75-1.68 (m, 2H)

Step 3—2-[3-(2-Methylsulfonyloxyethoxy)propoxy]ethyl Methanesulfonate

To a solution of 2-[3-(2-hydroxyethoxy)propoxy]ethanol (12.0 g, 73.0mmol) and TEA (44.3 g, 438 mmol) in DCM (160 mL) was added MsCl (25.1 g,219 mmol) dropwise at 0° C., then the mixture was stirred at 10° C. for1 hour. On completion, the reaction mixture was quenched by water (50mL) at 0° C., and then extracted with DCM (3×150 mL). The combinedorganic layers were washed with saturated citric acid (2×30 mL), driedover Na₂SO₄, filtered and concentrated in vacuo to give title compound(23 g, 98% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.67(t, J=4.4 Hz, 4H), 3.71 (t, J=4.4 Hz, 4H), 3.58 (t, J=6.0 Hz, 4H), 3.06(s, 6H), 1.93-1.79 (m, 2H).

Step4—2-[2-[3-[2-(1,3-Dioxoisoindolin-2-yl)ethoxy]propoxy]ethyl]isoindoline-1,3-dione

To a solution of 2-[3-(2-methylsulfonyloxyethoxy)propoxy]ethylmethanesulfonate (16.0 g, 49.9 mmol) in DMF (280 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (27.7 g, 149 mmol). The mixture wasstirred at 85° C. for 16 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give a residue. The residue wastriturated with EA (30 mL) and filtered to give a filter cake. Thefilter cake was triturated with water (150 mL) and filtered again togive the filter cake as the title compound (19 g, 90% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.87-7.78 (m, 8H), 3.67 (t, J=6.0 Hz,4H), 3.47 (t, J=6.0 Hz, 4H), 3.32 (t, J=6.0 Hz, 4H), 1.59-1.52 (m, 2H).

Step 5—2-[3-(2-Aminoethoxy)propoxy]ethanamine

To a solution of2-[2-[3-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]propoxy]ethyl]isoindoline-1,3-dione(18.0 g, 42.6 mmol) in EtOH (250 mL) was added NH₂NH₂ H₂O (21.7 g, 426mmol, 98% purity). The mixture was stirred at 80° C. for 16 hours. Oncompletion, the reaction mixture was filtered to give the filtrate whichwas concentrated in vacuo to give the title compound (7.2 g, 100% yield)as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 3.42 (t, J=6.4 Hz, 4H),3.31 (t, J=5.6 Hz, 4H), 2.63 (t, J=5.6 Hz, 4H), 2.46-2.09 (m, 4H),1.75-1.68 (m, 2H).

Step 6—Tert-butyl N-[2-[3-(2-aminoethoxy)propoxy]ethyl]carbamate

To a solution of 2-[3-(2-aminoethoxy)propoxy]ethanamine (7.20 g, 44.3mmol) in CHCl₃ (250 mL) was added a solution of (Boc)₂O (3.23 g, 14.7mmol) in CHCl₃ (80 mL) dropwise. The mixture was stirred at rt for 16hours. On completion, the reaction mixture was concentrated in vacuo togive a residue. The residue was purified by column chromatography (SiO₂)to give the title compound (2.50 g, 64% yield) as colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 4.98 (s, 1H), 3.54 (t, J=6.0 Hz, 4H), 3.51-3.42 (m,4H), 3.34-3.25 (m, 2H), 2.86 (t, J=5.2 Hz, 2H), 1.88-1.82 (m, 2H), 1.45(s, 9H).

Benzyl N-[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]carbamate(Intermediate KO)

Step 1—Methyl1-[4-(benzyloxycarbonylamino)phenyl]-4-nitro-pyrazole-3-carboxylate

To a solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (841 mg, 4.92mmol, CAS #1345513-95-2, Intermediate HL),[4-(benzyloxycarbonylamino)phenyl]boronic acid (2.00 g, 7.38 mmol, CAS#192804-36-7) in DCM (70.0 mL) was added pyridine (1.56 g, 19.6 mmol)and Cu(OAc)₂ (1.34 g, 7.38 mmol), and the mixture was stirred at rt for16 hrs under O₂ (15 psi). On completion, the mixture was concentrated invacuo. The mixture was purified by silica gel column (PE:EA=1:1) to givethe title compound (400 mg, 20% yield) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.14 (s, 1H), 7.50-7.45 (m, 2H), 7.40-7.36 (m, 2H), 7.35-7.30(m, 5H), 6.79 (s, 1H), 5.16 (s, 2H), 3.87 (s, 3H).

Step 2-Benzyl N-[4-(3-carbamoyl-4-nitro-pyrazol-1-yl)phenyl]carbamate

To a solution of methyl1-[4-(benzyloxycarbonylamino)phenyl]-4-nitro-pyrazole-3-carboxylate (200mg, 504 umol) in THF (10.0 mL) was added NH₃H₂O (4.55 g, 38.9 mmol, 30wt %), and the mixture was stirred at 110° C. for 16 hrs. On completion,the mixture was concentrated in vacuo. The mixture was purified byreverse phase: (0.1% FA) to give the title compound (70.0 mg, 36% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s, 1H), 9.54 (s,1H), 8.53 (s, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H),7.48-7.36 (m, 5H), 5.19 (s, 2H).

Step 3—Benzyl N-[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]carbamate

To a solution of benzylN-[4-(3-carbamoyl-4-nitro-pyrazol-1-yl)phenyl]carbamate (70.0 mg, 183umol) in MeOH (10.0 mL) and H₂O (5.00 mL) was added NH₄Cl (98.1 mg, 1.84mmol) and Zn (60.0 mg, 917 umol), and the mixture was stirred at rt for1 hr. On completion, the mixture was concentrated in vacuo. The mixturewas diluted with H₂O (10.0 mL) then extracted with EA (3×10 mL). Theorganic layers were dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (60.0 mg, 93% yield) asyellow solid, LC-MS (ESI⁺) m/z 352.1 (M+H)⁺

Tert-ButylN-[4-[4-[[1-(4-aminophenyl)-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(Intermediate KP)

Step 1—Tert-Butyl N-[4-[4-[[1-[4-(benzyloxycarbonylamino)phenyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of benzylN-[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]carbamate (60.0 mg, 170umol, Intermediate KO), and2-[2-[tertbutoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (92.0 mg, 256 umol, synthesized via Steps 1-4 of Intermediate DF)in DMF (3.00 mL) was added DIPEA (66.2 mg, 512 umol) and HATU (97.4 mg,256 umol), and the mixture was stirred at rt for 0.5 hr. On completion,the mixture was diluted with H₂O (15 mL) and extracted with EA (3×15mL). The organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The mixture was purified by reverse phase: (0.1%FA) to give the title compound (70.0 mg, 59% yield) as yellow solid.LC-MS (ESI⁺) m/z 693.2 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[1-(4-aminophenyl)-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of tert-butylN-[4-[4-[[1-[4-(benzyloxycarbonylamino)phenyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(70.0 mg, 101 umol) in THF (10.0 mL) was added Pd/C (30.0 mg), themixture was stirred at rt for 1 hr under H₂ (15 Psi). On completion, themixture was filtered and concentrated in vacuo to give the titlecompound (55.0 mg, 90% yield) as yellow solid. LC-MS (ESI⁺) m/z 559.4(M+H)⁺.

Methyl 4-amino-1-methyl-pyrazole-3-carboxylate (Intermediate KO)

To a solution of methyl 1-methyl-4-nitro-pyrazole-3-carboxylate (2 g,10.8 mmol, CAS #400877-57-8) in MeOH (20 mL) was added Pd/C (200 mg, 10%wt) under N₂ atmosphere. The suspension was degassed and purged with H₂gas 3 times. The mixture was stirred under H₂ (15 Psi) at rt for 12 hr.On completion, the reaction mixture was filtered and concentrated invacuo to give the title compound (1.68 g, 100% yield) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 6.95 (s, 1H), 3.92 (s, 3H), 3.86 (s, 3H).

4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylicAcid (Intermediate KR)

Step 1—Methyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylate

To a solution of methyl 4-amino-1-methyl-pyrazole-3-carboxylate (1.68 g,10.8 mmol, Intermediate KQ) and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (4.19 g, 10.8 mmol, Intermediate CM) in DMF (20 mL) was added DIPEA(2.80 g, 21.7 mmol), The reaction mixture was stirred at rt for 0.5 hr.After, HATU (4.94 g, 13.0 mmol) was added and the resulting reactionmixture was stirred at rt for 0.5 hr. On completion, the reactionmixture was quenched with water (200 mL). White precipitate formed afterthe reaction was added to water, which was filtered and the filteredcake was dried in vacuo to give the title compound (5.1 g, 90% yield) asa white solid; ¹H NMR (400 MHz, DMSO-d₆) δ 10.30 (s, 1H), 9.09 (s, 1H),8.65 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 7.76 (s, 1H), 4.93-4.86 (m,2H), 3.95 (s, 3H), 3.93 (s, 3H), 1.53 (s, 9H). LC-MS (ESI⁺) m/z 547.1(M+Na)⁺.

Step2—4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylic Acid

To a solution of methyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylate(500 mg, 953 umol) in a mixed solvent of THF (10 mL) and H₂O (2 mL) wasadded LiOH·H₂O (120 mg, 2.86 mmol). The reaction mixture was stirred atrt for 12 hrs. On completion, the reaction mixture was concentrated invacuo. The residue was diluted with water (50 mL) and acidified with HCl(2 N) to pH=5, then filtered. The filtered cake was collected, groundup, and dried for 2 hours at 105-110° C. in the drying oven. This wasthen ground again to a fine powder to give the title compound (480 mg,99% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1),9.07 (s, 1), 8.64 (d, J=4.8 Hz, 1H), 8.38 (s, 1), 8.24 (s, 1H), 7.77(dd, J=1.2, 5.2 Hz, 1H), 4.89 (q, J=8.8 Hz, 2H), 3.95 (s, 3H), 1.52 (s,9H).

4-[3-(3-Aminopropoxy)propylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate KS)

Step 1—Tert-ButylN-[3-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propoxyl]propyl]carbamate

To a mixture of tert-butyl N-[3-(3-aminopropoxy)propyl]carbamate (1.20g, 5.17 mmol, Intermediate EF) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (1.43 g, 5.17mmol, Intermediate R) in dioxane (50 mL) was added DIPEA (6.68 g, 51.6mmol, 9.00 mL). The reaction mixture was stirred at 115° C. for 12hours. On completion, the reaction mixture was concentrated in vacuo.The residue was purified by column chromatography (SiO2, PE:EA=1:1PE:EA=1:1, P1:Rf=0.08) to give the title compound (1.00 g, 39% yield) asyellow solid. LC-MS (ESI⁺) m/z 511.3 (M+Na)⁺.

Step2—4-[3-(3-Aminopropoxy)propylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[3-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propoxy]propyl]carbamate (1.20 g, 2.46 mmol) in DCM (10 mL) was addedHCl/dioxane (4 M, 20 mL). The reaction mixture was stirred at rt for 1hour. On completion, the reaction mixture was concentrated in vacuo togive the title compound (1.00 g, 95% yield, HCl) as yellow solid. LC-MS(ESI⁺) m/z 389.1 (M+H)⁺.

Tert-ButylN-[4-[4-[[1-(4-formylphenvl)-3-(methylcarbamoyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate KT)

Step1—1-[4-(Hydroxymethyl)phenyl]-N-methyl-4-nitro-pyrazole-3-carboxamide

To a solution of methyl1-[4-(hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carboxylate (200 mg, 721umol, synthesized via Step 1 of Intermediate GB) in THF (5.00 mL) wasadded MeNH₂ (2.00 M, 5.00 mL), and the mixture was stirred at 70° C. for16 hrs in a sealed tube. On completion, the mixture was concentrated invacuo. The mixture was diluted with H₂O (30 mL), then extracted with EA(3×30 mL). The organic layers were dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (195 mg, 97% yield)as yellow solid. 1H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H), 8.81-8.68 (m,1H), 7.97 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 2H), 5.39 (t, J=5.6 Hz,1H), 4.63 (d, J=5.6 Hz, 2H), 2.87 (d, J=4.8 Hz, 3H)

Step2—4-Amino-1-[4-(hydroxymethyl)phenyl]-N-methyl-pyrazole-3-carboxamide

To a solution of1-[4-(hydroxymethyl)phenyl]-N-methyl-4-nitro-pyrazole-3-carboxamide (195mg, 705 umol) in MeOH (100 mL) was added Pd/C (10 wt %, 100 mg), and themixture was purged with H₂ several times and stirred at 15° C. for 0.5hr under H₂ (15 psi). On completion, the mixture was filtered andconcentrated in vacuo to give the title compound (160 mg, 90% yield) asyellow solid. LC-MS (ESI⁺) m/z 247.1 (M+H)⁺.

Step 3—Tert-ButylN-[4-[4-[[1-[4-(hydroxymethyl)phenyl]-3-(methylcarbamoyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of4-amino-1-[4-(hydroxymethyl)phenyl]-N-methyl-pyrazole-3-carboxamide (160mg, 649 umol),2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (251 mg, 649 umol, Intermediate CM) in DMF (3.00 mL) was addedDIPEA (251 mg, 1.95 mmol) and HATU (296 mg, 779 umol), and the mixturewas stirred at rt for 0.5 hr. On completion, the mixture was dilutedwith H₂O (1.00 mL) and concentrated in vacuo. The mixture was purifiedby reverse phase chromatography (0.1% NH₃H₂O) to give the title compound(200 mg, 50% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08(s, 1H), 9.10 (s, 1H), 8.93 (s, 1H), 8.67 (d, J=5.2 Hz, 1), 8.62-8.56(m, 1), 8.29 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.82-7.77 (m, 1H), 7.50(d, J=8.8 Hz, 2H), 5.30 (t, J=5.6 Hz, 1H), 4.96-4.86 (m, 2H), 4.57 (d,J=5.6 Hz, 2H), 2.87 (d, J=4.8 Hz, 3H), 1.56 (s, 9H).

Step 4—Tert-ButylN-[4-[4-[[1-(4-formylphenyl)-3-(methylcarbamoyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[1-[4-(hydroxymethyl)phenyl]-3-(methylcarbamoyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(110 mg, 178 umol) in THF (20.0 mL) was added DMP (90.9 mg, 214 umol),and the mixture was stirred at rt for 1 hr. On completion, the mixturewas quenched with saturated Na₂S₂O₃ (30 mL) and washed with saturatedNaHCO₃ (2×30 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (105 mg,90% yield) as yellow solid. LC-MS (ESI⁺) m/z 614.3 (M+H)⁺.

1-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]ethenone(Intermediate KU)

Step 1—1-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]phenyl]ethanone

To a mixture of 3-(difluoromethyl)-4-nitro-1H-pyrazole (1.42 g, 8.69mmol, Intermediate HS), 1-(4-fluorophenyl) ethanone (1.0 g, 7.24 mmol)in DMF (10 mL) was added K₂CO₃ (1.50 g, 10.8 mmol). The reaction mixturewas stirred at 120° C. for 12 hours. On completion, the mixture wasconcentrated in vacuo. The residue was purified by column chromatography(SiO₂) to give the title compound (435 mg, 21% yield) as brown oil.¹HNMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H), 8.17-8.13 (m, 4H), 7.59-7.32(m, 1H), 2.64 (s, 3H).

Step 2—1-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]ethanone

To a mixture of1-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]phenyl]ethanone (360 mg,1.28 mmol) in MeOH (20 mL) and H₂O (10 mL) was added Zn (837 mg, 12.8mmol) and AcOH (769 mg, 12.8 mmol). The reaction mixture was stirred atrt for 1 hour. On completion, the mixture was concentrated in vacuo togive the title compound (186 mg, 58% yield) as a yellow solid. LC-MS(ESI⁺) m/z 252.2 (M+H)

Tert-ButylN-[4-[4-[[1-(4-acetylphenyl)-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(Intermediate KV)

To a mixture of1-[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]ethanone (90 mg, 358umol, Intermediate KU),2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (154 mg, 429 umol, synthesized via Steps 1-4 of Intermediate DF) inDMF (10 mL) was added DIPEA (139 mg, 1.07 mmol) and HATU (163 mg, 430umol). The mixture and stirred at rt for 2 hours. On completion, themixture was concentrated in vacuo. The residue was purified byreversed-phase HPLC (0.1% FA condition) to give the title compound (165mg, 75% yield) as a white solid. LC-MS (ESI⁺) m/z 593.2 (M+H)⁺.

Methyl4-(4-amino-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-1-yl)benzoate(Intermediate KW)

Step 1—Methyl4-(3-(3-hydroxyprop-1-yn-1-yl)-4-nitro-1H-pyrazol-1-yl)benzoate

Methyl 4-(3-bromo-4-nitro-pyrazol-1-yl)benzoate (1 g, 3.07 mmol,Intermediate JS), prop-2-yn-1-ol (500 mg, 8.92 mmol), Pd(PPh₃)₂Cl₂ (215mg, 307 umol), TEA (3.10 g, 30.7 mmol), and CuI I (58.4 mg, 307 umol)were taken up into a microwave tube in DMF (10 mL) under N₂. Thereaction mixture was de-gassed with N₂ and then the sealed tube washeated to 80° C. for 0.5 hour. On completion, the reaction mixture wasconcentrated in vacuo. The crude product was purified by silica gelchromatography (PE:EA=2:1) to give the title compound (920 mg, 100%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ9.87 (s, 1), 8.18(s, 4H), 5.62 (t, J=6.0 Hz, 1), 5.49-5.43 (m, 1), 4.47 (d, J=6.0 Hz,2H), 3.94 (s, 3H).

Step 2—Methyl4-(4-nitro-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)-1H-pyrazol-1-yl)benzoate

To a solution of methyl4-[3-(3-hydroxyprop-1-ynyl)-4-nitro-pyrazol-1-yl]benzoate (600 mg, 1.99mmol) and DHP (251 mg, 2.99 mmol) in a mixed solvent of DCM (100 mL) andTHF (20 mL) was added PPTS (50.1 mg, 199 umol). The reaction mixture wasstirred at rt for 12 hours under N₂. On completion, the reaction mixturewas concentrated in vacuo. The crude product purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1) to give thetitle compound (700 mg, 91% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.83 (s, 1H), 8.13 (s, 4H), 4.94-4.86 (m, 1H), 4.66-4.50 (m,2H), 3.90 (s, 3H), 3.79 (ddd, J=3.2, 8.4, 11.2 Hz, 1H), 3.57-3.47 (m,1H), 1.75-1.65 (m, 2H), 1.59-1.49 (m, 4H). LC-MS (ESI⁺) m/z 408.1(M+Na)⁺.

Step 3—Methyl4-(4-amino-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-1-yl)benzoate

To a solution of methyl4-[4-nitro-3-(3-tetrahydropyran-2-yloxyprop-1-ynyl)pyrazol-1-yl]benzoate(930 mg, 2.41 mmol) in MeOH (10 mL) was added Pd/C (50 mg, 10 wt %) andPd(OH)₂/C (50 mg, 10 wt %) under N₂ atmosphere. The suspension wasdegassed and purged with H₂ gas 3 times. The mixture was stirred underH₂ (15 Psi) at rt for 24 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give the title compound (760 mg,88% yield) as a yellow solid. LC-MS (ESI⁺) m/z 360.2 (M+H)⁺.

4-(4-(2-(2-((Tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-1-yl)benzoicacid (Intermediate KX)

Step 1—Tert-Butyl4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]piperidine-1-carboxylate

To a solution of2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazolecarboxylic acid (711 mg, 1.84 mmol, Intermediate CM) and methyl4-[4-amino-3-(3-tetrahydropyran-2-yloxypropyl)pyrazol-1-yl] benzoate(660 mg, 1.84 mmol, Intermediate KW) in DMF (5 mL) was added DIPEA (475mg, 3.67 mmol), and the reaction mixture was stirred at rt for 0.5 hour.Then, HATU (838 mg, 2.20 mmol) was added and the resulting reactionmixture was stirred at rt for an additional 0.5 hour. On completion, thereaction mixture was quenched with water (50 mL) and filtered. Thefiltered cake was collected and dried over high vacuum to give (800 mg,60% yield) as a yellow solid. LC-MS (ESI⁺) m/z 729.1 (M+H)⁺.

Step2—4-(4-(2-(2-((Tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-1-yl)benzoicacid

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(3-tetrahydropyran-2-yloxypropyl)pyrazol-1-yl]benzoate(800 mg, 1.10 mmol) in a mixed solvent of THF (9 mL) and H₂O (3 mL) wasadded LiOH·H₂O (138 mg, 3.29 mmol). The reaction mixture was stirred atrt for 12 hours. On completion, the reaction mixture was concentrated invacuo to removed THF then diluted with water (10 mL) and acidified with2 N aq.HCl to pH=5, then extracted with ethyl acetate (3×50 mL). Thecombined organic layer was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the titlecompound (740 mg, 94% yield) as a yellow solid. LC-MS (ESI⁺) m/z 715.1(M+H)⁺.

Tert-Butyl(4-(4-((1-(4-formylphenyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate(Intermediate KY)

Step1—4-(4-(2-(2-((Tert-butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-1-yl)benzoic(isopropyl carbonic) Anhydride

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(3-tetrahydropyran-2-yloxypropyl)pyrazol-1-yl]benzoicacid (740 mg, 1.04 mmol, Intermediate KX) in THF (20 mL) was added TEA(419 mg, 4.14 mmol). Then, the reaction mixture was cooled to −10° C.and isopropyl carbonochloridate (254 mg, 2.07 mmol) was added. Theresulting reaction mixture was stirred at −10° C. for 2 hours. Oncompletion, the reaction mixture was filtered. The filtrate wasconcentrated in vacuo to give the title compound (800 mg, 96% yield) asa white solid. LC-MS (ESI⁺) m/z 801.1 (M+H)⁺.

Step 2—Tert-Butyl(4-(4-((1-(4-(hydroxymethyl)phenyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

To a solution of isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(3-tetrahydropyran-2-yloxypropyl)pyrazol-1-yl]benzoate(800 mg, 999 umol) in THF (50 mL) was added H₂O (180 mg, 9.99 mmol) andLiBH₄ (109 mg, 5.00 mmol). The reaction mixture was stirred at 0° C. for10 minutes. On completion, the mixture was quenched with water (5 mL)and was extracted with DCM (3×50 mL). The combined organic layer waswashed with brine (20 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to give the title compound (700 mg, 100%yield) as a white solid. LC-MS (ESI⁺) m/z 701.1 (M+H)⁺.

Step 3—Tert-butyl(4-(4-((1-(4-formylphenyl)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[1-[4-(hydroxymethyl)phenyl]-3-(3-tetrahydropyran-2-yloxypropyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(700 mg, 999 umol) in DCM (20 mL) was added DMP (847 mg, 2.00 mmol). Thereaction mixture was stirred at rt for 2 hours. On completion, thereaction mixture was quenched with water (1 mL) and was concentrated invacuo. The crude product was purified by prep-HPLC (condition: 0.1% FA)to give the title compound (270 mg, 30% yield) as colorless solid. LC-MS(ESI⁺) m/z 699.1 (M+H)⁺.

[4-[1-(Tert-butoxycarbonylamino)cyclopropyl]phenyl]boronic acid(Intermediate KZ)

Step 1—Tert-ButylN-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]carbamate

A mixture of tert-butyl N-[1-(4-bromophenyl)cyclopropyl]carbamate (3 g,9.61 mmol, CAS #360773-84-8), Pin₂B₂ (4.88 g, 19.2 mmol), KOAc (2.83 g,28.8 mmol) and cyclopentyl(diphenyl) phosphane; dichloromethane;dichloropalladium; iron (392 mg, 480 umol) in DMSO (30 mL) was degassedand then heated to 70° C. for 12 hours under N₂. On completion, themixture was quenched with water (200 mL) and filtered. The filter cakewas purified by silica gel chromatography (SiO₂) to give the titlecompound (3.0 g, 87% yield) as a white solid. LC-MS (ESI⁺) m/z 398.2(M+K)⁺.

Step 2—[4-[1-(Tert-butoxycarbonylamino)cyclopropyl]phenyl]boronic Acid

To a solution of tert-butylN-[1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropyl]carbamate (1.2 g, 3.34 mmol) in a mixed solvent of THF (30 mL) and H₂O(6 mL) was added NaIO₄ (2.14 g, 10.0 mmol). The reaction mixture wasstirred at rt for 0.5 hour. Then, HCl (3 M, 2.23 mL) was added and themixture was stirred at rt for 4 hrs. On completion, the mixture wasdiluted with water, then extracted with EA (30 mL×2). The organic layerwas washed with water and concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(0.76 g, 82% yield) as a white solid. LC-MS (ESI⁺) m/z 278.1 (M+H)⁺.

Tert-ButylN-[1-[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]cyclopropyl]carbamate(Intermediate LA)

Step 1—Tert-ButylN-[1-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]phenyl]cyclopropyl]carbamate

To a solution of[4-[1-(tert-butoxycarbonylamino)cyclopropyl]phenyl]boronic acid (0.76 g,2.74 mmol, Intermediate KZ) and 3-(difluoromethyl)-4-nitro-1H-pyrazole(447 mg, 2.74 mmol, Intermediate HS) in DCM (10 mL) was added Cu(OAc)₂(747 mg, 4.11 mmol) and pyridine (4.34 g, 54.9 mmol). The reactionmixture was stirred at rt for 10 hours under oxygen (15 Psi) atmosphere.On completion, the mixture was concentrated in vacuo. The residue waspurified by silica gel chromatography (SiO₂), then the residue wasrepurified by reverse phase (0.1% FA condition) to give the titlecompound (550 mg, 51% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.71 (s, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.56-7.27 (m, 3H),1.43-1.25 (m, 9H), 1.22-1.17 (m, 4H); LC-MS (ESI⁺) m/z 339.0 (M−56+H)⁺.

Step 2—Tert-butylN-[1-[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]cyclopropyl]carbamate

To a solution of tert-butylN-[1-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]phenyl]cyclopropyl]carbamate (0.55 g, 1.39 mmol) in THF (10 mL) was added Pd/C (0.2 g, 10wt %). The reaction mixture was stirred at rt for 4 hours under H₂ (15Psi) atmosphere. On completion, the mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (0.42 g,83% yield) as a yellow solid. LC-MS (ESI⁺) m/z 365.1 (M+H)⁺.

N-[1-[4-(1-aminocyclopropyl)phenyl]-3-(difluoromethyl)pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide(Intermediate LB)

Step 1—Tert-ButylN-[4-[4-[[1-[4-[1-(tert-butoxycarbonylamino)cyclopropyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of tert-butylN-[1-[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]phenyl]cyclopropyl]carbamate (220 mg, 604 umol, Intermediate LA) and2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylic acid (217 mg, 604 umol, synthesized via Steps 1-4of Intermediate DF) in DMF (5 mL) was added DIPEA (234 mg, 1.81 mmol)and HATU (276 mg, 725 umol). The reaction mixture was stirred at rt for0.5 hour. On completion, the mixture was quenched with water (50 mL),filtered and the filter cake was dried in vacuo to give the titlecompound (0.27 g, 63% yield) as a brown solid. LC-MS (ESI⁺) m/z 706.4(M+H)⁺.

Step2—N-[1-[4-(1-aminocyclopropyl)phenyl]-3-(difluoromethyl)pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[1-[4-[1-(tert-butoxycarbonylamino)cyclopropyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(250 mg, 354 umol) in DCM (1 mL) was added 4.0 M HCl/dioxane (1 mL). Thereaction mixture was stirred at rt for 10 hours. On completion, themixture was concentrated in vacuo to give the title compound (0.19 g,99% yield, HCl) as a light yellow solid. LC-MS (ESI⁺) m/z 506.2 (M+H)⁺.

2-(2-Prop-2-ynoxyethoxy)ethanol (Intermediate LC)

To a mixture of t-BuOK (4.76 g, 42.5 mmol) in THF (120 mL) was added2-(2-hydroxyethoxy)ethanol (8.92 g, 84.0 mmol, CAS #111-46-4) at 0° C.The reaction mixture was stirred at rt for 30 minutes and then3-bromoprop-1-yne (5 g, 42.0 mmol) in THF (25 mL) was added dropwise.The reaction mixture was stirred at rt for 12 hours. On completion, themixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatography (SiO₂) to give thetitle compound (3 g, 50% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ4.20 (d, J=2.4 Hz, 2H), 3.76-3.65 (m, 6H), 3.63-3.56 (m, 2H), 2.44 (t,J=2.4 Hz, 1H), 2.41 (s, 1H).

2,2-Dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl4-methylbenzenesulfonate (Intermediate LD)

To a stirred solution of tert-butyl(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)ethyl)carbamate (8 g, 27.30mmol, synthesized via Step 1 of Intermediate EN) in DCM (100 mL) wasadded TEA (5.52 g, 54.60 mmol) at rt. To the above reaction mixture wasadded dropwise TsCl (10.41 g, 54.60 mmol) in DCM (5 mL) at 0° C. Afterthe addition, the reaction mixture was stirred at rt overnight. Themixture was concentrated in vacuo and the residue was purified viacolumn chromatography (Petroleum ether/EtOAc=5%-80%) to give the titlecompound (10.9 g, 73%) as a yellow oil. LC-MS (ESI⁺): m/z 448.3 (M+H)⁺.

2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]acetaldehyde(Intermediate LE)

Step1—3-[4-[3-[2-(2-hydroxyethoxy)ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

2-(2-prop-2-ynoxyethoxy)ethanol (384 mg, 2.66 mmol, Intermediate LC),CuI (84.5 mg, 444 umol) and Pd(PPh₃)₂Cl₂ (311 mg, 444 umol) was taken upinto a tube. Then 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300 mg, 887 umol, Intermediate HP), TEA (1.62 g,16 mmol) and DMF (5 mL) were added into the above tube. The mixture wasdegassed with N₂ and the sealed tube was heated at 80° C. for 2 hours.On completion, the mixture was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(0.12 g, 34% yield) as a brown solid. LC-MS (ESI⁺) m/z 402.1 (M+H)⁺.

Step2—3-[4-[3-[2-(2-hydroxyethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-[4-[3-[2-(2-hydroxyethoxy)ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(50 mg, 125 umol) in THF (4 mL) was added Pd/C (0.1 g, 10 wt %) andPd(OH)₂/C (0.1 g, 10 wt %). The reaction mixture was stirred at rt for10 hours under H₂ (15 Psi) atmosphere. On completion, the mixture wasfiltered and filtrate was concentrated in vacuo to give the titlecompound (50 mg, 99% yield) as yellow oil. LC-MS (ESI⁺) m/z 406.1(M+H)⁺.

Step3—2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]acetaldehyde

To a solution of3-[4-[3-[2-(2-hydroxyethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (50 mg, 123 umol) in THF (3 mL) was added DMP (78.5mg, 185 umol). The reaction mixture was stirred at rt for 2 hours. Oncompletion, the mixture was quenched with sat. Na₂S₂O₃ (20 mL) and sat.NaHCO₃ (20 mL) and stirred for 0.5 hour. The reaction mixture was thenextracted with DCM (2×30 mL). The organic layer was washed with brine(40 mL), dried over Na₂SO₄, filtered and the filtrate was concentratedin vacuo to give the title compound (30 mg, 60% yield) as yellow oil.LC-MS (ESI⁺) m/z 404.2 (M+H)⁺.

3-[4-[3-(3-aminopropoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate LF)

Step 1—Tert-ButylN-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propyl]carbamate

To a stirred solution of3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(221 mg, 0.65 mmol,), tert-butylN-[3-(prop-2-yn-1-yloxy)propyl]carbamate (209 mg, 0.98 mmol,Intermediate OH) and TEA (1 mL) in DMA (3 mL) were added CuI (12.4 mg,0.07 mmol) and Pd(PPh₃)₂Cl₂ (45.9 mg, 0.07 mmol) at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred for 2 h at90° C. The mixture was cooled down to room temperature and concentratedunder reduced pressure to remove TEA. The residue was purified byreverse phase flash chromatography with the following conditions:Column: WelFlash™ C18-1, 20-40 μm, 80 g; Eluent A: Water (plus 10 mmol/LFA); Eluent B: ACN; Gradient: 35%-55% B in 15 min; Flow rate: 50 mL/min;Detector: 220/254 nm; desired fractions were collected at 50% B andconcentrated under reduced pressure to afford tert-butylN-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propyl]carbamate(90 mg, 29%) as a light pink solid. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s,1H), 7.20 (d, J=7.9 Hz, 1H), 7.01 (t, J=7.9 Hz, 1H), 6.78 (d, J=7.9 Hz,1H), 5.22 (dd, J=12.5, 5.3 Hz, 1H), 4.80 (s, 1H), 4.42 (s, 2H), 3.80 (s,3H), 3.68 (t, J=6.0 Hz, 2H), 3.30-3.24 (m, 2H), 3.02-2.95 (m, 1H),2.91-2.69 (m, 2H), 2.28-2.26 (m, 1H), 1.85 (q, J=6.2 Hz, 2H), 1.46 (s,9H); LC/MS (ESI, m/z): [(M−1)]⁻=469.5.

Step 2—Tert-butylN-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propyl)carbamate

To a stirred solution of tert-butylN-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propyl]carbamate(0.5 g, 1.06 mmol) in THF (10 mL) was added palladium on charcoal (100mg, 10% w/w) at room temperature under nitrogen atmosphere. Theresulting mixture was purged with H₂ gas 3 times and stirred for 16 h atroom temperature under hydrogen atmosphere. The reaction mixture wasfiltered through a Celite pad. The filtrate was concentrated underreduced pressure to afford tert-butylN-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propyl)carbamate(430 mg, 85%) as a light green oil. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s,1H), 7.01 (t, J=7.8 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.69 (d, I=7.7 Hz,1H), 5.22 (dd, J=12.3, 5.5 Hz, 1H), 4.88 (s, 1H), 3.77 (s, 1H), 3.71 (s,3H), 3.50 (m, 3H), 3.26 (d, J=6.3 Hz, 2H), 3.08-3.00 (m, 2H), 3.00-2.91(m, 1H), 2.91-2.71 (m, 2H), 2.32-2.19 (m, 1H), 2.00-1.74 (m, 4H), 1.46(s, 9H); LC/MS (ESI, m/z): [(M−1)]⁻=473.3.

Step3—3-[4-[3-(3-Aminopropoxy)propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride

To a stirred solution of tert-butylN-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propyl)carbamate(430 mg, 0.91 mmol) in 1,4-dioxane (5 mL) was added a solution of HCl in1,4-dioxane (4 M, 5 mL) dropwise at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 3 h at room temperature. The resultingmixture was concentrated under reduced pressure and the residue wasdissolved in 1,4-dioxane (15 mL) and re-concentrated under reducedpressure to afford3-[4-[3-(3-aminopropoxy)propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride (310 mg, 910%) as a brown yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 7.94 (s, 3H), 7.02-6.92 (m, 2H), 6.88 (dd,J=6.4, 2.5 Hz, 1H), 5.39 (dd, J=12.6, 5.4 Hz, 1H), 3.60-3.54 (s, 3H),3.51-3.43 (m, 4H), 3.02-2.82 (m, 5H), 2.79-2.58 (m, 2H), 2.09-1.93 (m,1H), 1.90-1.80 (m, 4H); LC/MS (ESI, m/z): [(M+1)]⁺=375.3.

3-[5-[3-(3-aminopropoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate LG)

Step 1—Tert-ButylN-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)propyl]carbamate

To a stirred mixture of3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(2 g, 6 mmol, Intermediate HN), Pd(PPh₃)₄ (683.4 mg, 0.59 mmol) and CuI(225.3 mg, 1.18 mmol) in DMSO (10 mL) and TEA (5 mL) was addedtert-butyl N-[3-(prop-2-yn-1-yloxy)propyl]carbamate (3.8 g, 18 mmol,Intermediate OH) at room temperature under nitrogen atmosphere. Theresulting mixture was purged with nitrogen three times and stirred for16 h at 90° C. under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure to remove TEA. The resulting mixturewas diluted with a solution of AcOH (3 mL) in ice water (50 mL) andextracted with EtOAc (2×50 mL). The combined organic layers was washedwith brine (30 mL) and dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by reverse phase flash chromatography with the followingconditions: Column: WelFlash™ C18-1, 20-40 m, 330 g; Eluent A: Water(plus 10 mmol/L FA); Eluent B: ACN; Gradient: 50%-60% B in 20 min; Flowrate: 80 mL/min; Detector: 220/254 nm; desired fractions were collectedat 57% B and concentrated under reduced pressure to afford tert-butylN-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)propyl]carbamate(1.5 g, 54%) as a light yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.12(s, 1H), 7.34 (s, 1H), 7.23-7.11 (m, 2H), 6.80 (s, 1H), 5.40 (dd,J=12.7, 5.4 Hz, 1H), 4.35 (s, 2H), 3.51 (t, J=6.4 Hz, 2H), 3.35 (s, 3H),3.00 (q, J=6.7 Hz, 2H), 2.95-2.83 (m, 1H), 2.79-2.58 (m, 2H), 2.03 (dd,J=9.3, 4.3 Hz, 1H), 1.66 (p, J=6.6 Hz, 2H), 1.37 (s, 9H); LC/MS (ESI,m/z): [(M+1)]⁺=469.20.

Step 2—Tert-ButylN-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]propyl)carbamate

To a stirred solution of tert-butylN-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)propyl]carbamate(800 mg, 1.70 mmol) in THF (20 mL) was added palladium on charcoal (200mg, 10% w/w) at rt under nitrogen atmosphere. The resulting mixture waspurged with H₂ gas 3 times and stirred for 4 h at room temperature underhydrogen atmosphere. The reaction mixture was filtered through a Celitepad. The filtrate was concentrated under reduced pressure to affordtert-butylN-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]propyl)carbamate(730 mg, 90%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 7.06-6.97 (m, 2H), 6.87 (d, J=7.8 Hz, 1H), 6.77 (s, 1H), 5.34 (dd,J=12.7, 5.3 Hz, 1H), 3.61 (s, 1H), 3.40-3.31 (m, 6H), 2.99 (q, J=6.6 Hz,2H), 2.90 (t, J=15.0 Hz, 1H), 2.73-2.58 (m, 4H), 2.01 (d, J=12.7 Hz,1H), 1.83-1.73 (m, 2H), 1.66-1.58 (m, 2H), 1.38 (s, 9H); LC/MS (ESI,m/z): [(M−1)]⁻=473.3.

Step3—3-[5-[3-(3-Aminopropoxy)propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride

To a stirred solution of tert-butylN-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]propyl)carbamate(730 mg, 1.54 mmol) in 1,4-dioxane (10 mL) was added a solution of HClin dioxane (4 M, 10 mL) dropwise at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 16 h at rt under nitrogen atmosphere.The resulting mixture was concentrated under reduced pressure. Theresidue was dissolved in 1,4-dioxane (20 mL) and re-concentrated underreduced pressure to afford3-[5-[3-(3-aminopropoxy)propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride (600 mg, 99%) as a light brown solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 7.74 (br s, 3H), 7.11-6.95 (m, 2H), 6.87 (d,J=8.0 Hz, 1H), 5.35 (dd, J=12.8, 5.4 Hz, 1H), 3.58 (s, 3H), 3.44 (t,J=6.1 Hz, 2H), 3.39 (t, J=6.5 Hz, 2H), 2.94-2.80 (m, 3H), 2.77-2.56 (m,4H), 2.10-1.95 (m, 1H), 1.90-1.76 (m, 4H); LC/MS (ESI, m/z):[(M+1)]⁺=375.10.

3-(4-(3-(3-(3-Aminopropoxy)propoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(Intermediate LH)

Step 1—Tert-ButylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate

To a solution of3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(2 g, 5.91 mmol, Intermediate HP) in DMA (30 mL) were added tert-butylN-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (3 g, 11.06 mmol,Intermediate OJ), TEA (15 mL), CuI (113 mg, 0.59 mmol) and Pd(PPh₃)₄(0.68 g, 0.59 mmol) at rt under nitrogen atmosphere. The resultingmixture was stirred for 5 h at 90° C. under nitrogen atmosphere. Theresulting mixture was cooled down to rt and concentrated under reducedpressure. The residue was purified by reverse phase flash chromatographywith the following conditions: Column: WelFlash™ C18-1, 20-40 μm, 330 g;Eluent A: Water (plus 10 mmol/L HCOOH); Eluent B: ACN; Gradient: 35%-60%B in 15 min; Flow rate: 80 mL/min; Detector: 220/254 nm; desiredfractions were collected at 55% B and concentrated under reducedpressure to afford tert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate(1.4 g, 45%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12(br s, 1H), 7.19-7.12 (m, 2H), 7.08-6.95 (m, 1H), 6.75 (br s, 1H), 5.41(dd, J=12.7, 5.4 Hz, 1H), 4.43 (s, 2H), 3.64 (s, 3H), 3.63-3.55 (m, 4H),3.42 (t, J=6.4 Hz, 2H), 3.35 (d, J=12.6 Hz, 2H), 3.00-2.83 (m, 3H), 2.71(m, 2H), 2.10-1.97 (m, 2H), 1.78 (p, J=6.4 Hz, 2H), 1.59 (p, J=6.6 Hz,2H), 1.37 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=529.35.

Step 2—Tert-ButylN-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propoxy)propyl]carbamate

To a stirred solution of tert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate(900 mg, 1.71 mmol) in THF (20 mL) was added palladium on charcoal (300mg, 10% w/w) at rt under nitrogen atmosphere. The resulting mixture waspurged with hydrogen for 3 times and was stirred for 4 h at rt underhydrogen atmosphere. The reaction mixture was filtered through a Celitepad. The filtrate was concentrated under reduced pressure to affordtert-butylN-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propoxy)propyl]carbamate(800 mg, 88%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10(br s, 1H), 7.02-6.98 (m, 2H), 6.90-6.83 (m, 1H), 6.76 (t, J=5.7 Hz,1H), 5.37 (dd, J=12.6, 5.4 Hz, 1H), 3.56 (s, 3H), 3.52-3.33 (m, 6H),3.01-2.83 (m, 5H), 2.72-2.58 (m, 2H), 2.00 (ddd, J=11.1, 5.9, 3.6 Hz,1H), 1.89-1.68 (m, 6H), 1.60 (p, J=6.6 Hz, 2H), 1.37 (s, 9H); LC/MS(ESI, m/z): [(M+1)]⁺=533.40.

Step3—3-(4-[3-[3-(3-Aminopropoxy)propoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride

To a stirred solution of tert-butylN-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propoxy)propyl]carbamate(800 mg, 1.50 mmol) in 1,4-dioxane (10 mL) was added a solution ofhydrochloride in dioxane (4 M, 10 mL) dropwise at 0° C. The resultingmixture was stirred for 2 h at rt. The resulting mixture wasconcentrated under reduced pressure to afford3-(4-[3-[3-(3-aminopropoxy)propoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride (640 mg, 91%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.11 (br s, 1H), 7.83 (br s, 3H), 7.05-6.93 (m, 2H), 6.88 (td, J=6.8,5.9, 3.1 Hz, 1H), 5.38 (dd, J=12.5, 5.4 Hz, 1H), 3.57 (s, 3H), 3.45-3.31(m, 8H), 3.04-2.77 (m, 5H), 2.77-2.57 (m, 2H), 1.99 (dd, J=9.8, 4.9 Hz,1H), 1.90-1.70 (m, 6H); LC/MS (ESI, m/z): [(M+1)]⁺=433.30.

3-(5-[3-[3-(3-Aminopropoxy)propoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(Intermediate LI)

Step 1—Tert-ButylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate

To a stirred solution of3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(2.0 g, 5.91 mmol, Intermediate HN) in DMSO (20 mL) were addedtert-butyl N-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (5.8 g,21.4 mmol, Intermediate OJ), TEA (10 mL), CuI (0.2 g, 1 mmol) andPd(PPh₃)₄ (0.7 g, 0.59 mmol) at rt under nitrogen atmosphere. Theresulting mixture was stirred for 3 h at 90° C. The resulting mixturewas cooled to rt and concentrated under reduced pressure. The resultingmixture was diluted with 1% aqueous solution of AcOH (100 mL) andextracted with EtOAc (2×100 mL). The combined organic layers was washedwith brine (100 mL) and dried over anhydrous Na₂SO₄. After filtration,the filtrate was concentrated under reduced pressure. The residue waspurified by reverse phase flash chromatography with the followingconditions: Column: WelFlash™ C18-1, 20-40 μm, 330 g; Eluent A: Water(plus 10 mmol/L AcOH); Eluent B: ACN; Gradient: 45%-55% B in 10 min;Flow rate: 80 mL/min; Detector: 220/254 nm; desired fractions werecollected at 51% B and concentrated under reduced pressure to affordtert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate(1.5 g, 48%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (br s,1H), 7.22 (dd, J=8.2, 1.5 Hz, 1H), 7.14 (d, J=1.4 Hz, 1H), 6.77 (d,J=8.1 Hz, 1H), 5.22 (dd, J=12.7, 5.3 Hz, 1H), 4.89 (br s, 1H), 4.39 (s,2H), 3.69 (t, J=6.3 Hz, 2H), 3.55 (t, J=6.3 Hz, 2H), 3.51 (t, J=5.9 Hz,2H), 3.44 (s, 3H), 3.23 (q, J=6.1 Hz, 2H), 3.03-2.64 (m, 3H), 2.34-2.24(m, 1H), 1.92 (p, J=6.3 Hz, 2H), 1.76 (p, J=6.3 Hz, 2H), 1.46 (s, 9H);LC/MS (ESI, m/z): [(M+1)]+=529.25.

Step 2—Tert-ButylN-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]propoxy)propyl]carbamate

To a solution of tert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate(200 mg, 0.38 mmol) in THF (10 mL) was added palladium on charcoal (402mg, 10% w/w) under nitrogen atmosphere. The mixture was purged withhydrogenated for three times and was stirred at rt for 6 h underhydrogen atmosphere. The resulting mixture was filtered through a Celitepad and the filtrate was concentrated under reduced pressure to affordtert-butylN-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]propoxy)propyl]carbamate(150 mg, 74%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (br s,1H), 7.93 (br s, 1H), 7.06-6.98 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 5.36(dt, J=12.6, 6.0 Hz, 1H), 3.57 (s, 5H), 3.47-3.34 (m, 8H), 3.04-2.84 (m,2H), 2.82-2.66 (m, 1H), 2.66-2.58 (m, 3H), 2.04-1.96 (m, 1H), 1.86-1.68(m, 4H), 1.65-1.53 (m, 1H), 1.37 (s, 9H); LC/MS (ESI, m/z):[(M+1)]⁺=533.25.

Step3—3-(5-[3-[3-(3-Aminopropoxy)propoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride

To a solution of tert-butylN-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]propoxy]propoxy)propyl]carbamate(300 mg, 0.56 mmol) in dioxane (10 mL) was added a solution ofhydrochloride in 1,4-dioxane (4 M, 10 mL). The resulting solution wasstirred for 4 h at rt under nitrogen atmosphere. The resulting mixturewas concentrated under vacuum to afford3-(5-[3-[3-(3-aminopropoxy)propoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride (200 mg, 76%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.09 (br s, 1H), 7.93 (br s, 3H), 7.06-6.99 (m, 2H), 6.87 (d, J=8.0Hz, 1H), 5.36 (dd, J=12.7, 5.5 Hz, 1H), 3.58 (s, 3H), 3.48-3.34 (m, 8H),3.02-2.54 (m, 7H), 2.00 (dd, J=11.4, 6.2 Hz, 1H), 1.87-1.68 (m, 6H);LC/MS (ESI, m/z): [(M+1)]⁺=433.15.

3-Bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (Intermediate LJ)

Step 1—3-bromopiperidine-2,6-dione

To a stirred solution of piperidine-2,6-dione (30 g, 0.266 mol) in CHCl₃(60 mL) was added Br₂ (13.5 mL, 0.265 mol) in a sealed glass tube, thenthe reaction mixture was heated to 113° C. for 1.5 h. The mixture wascooled to r.t. and transferred to a round bottom flask and concentrated.To the residue was added 100 mL ice water, and the solution was basifiedto pH=8 with saturated NaHCO₃ aqueous, then extracted with DCM (100mL×5). The organic layer was dried with Na₂SO₄, filtered, andconcentrated to give crude product, which was dissolved in a solution ofDCM:EtOAc=1:1 (˜90 mL), then heated to 80° C. After the solid wascompletely dissolved, the heating was stopped and the solution wascooled to r.t. for overnight. The solution was filtered, the solid wascollected, and dried under vacuum to give desired compound (15.7 g) as awhite solid. The filtrate was also concentrated to dry to give crudeproduct, which was purified by column chromatography on silica geleluting with DCM:Petroleum ether:EtOAc=5:5:1 to DCM:Petroleumether:EtOAc=5:5:2 to obtain desired the second batch pure product (12 g)as a white solid (total yield: 54.5%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.06(s, 1H), 5.00-4.78 (m, 1H), 2.69-2.54 (m, 2H), 2.45 (dd, J=10.0, 5.1 Hz,1H), 2.17-2.12 (m, 1H).

Step 2—3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 3-bromopiperidine-2,6-dione (30 g, 156.3 mmol),(4-methoxyphenyl)methanol (23.3 g, 168 mmol) and PPh₃ (40.5 g, 154.5mmol) in dry THF (450 mL) was added dropwise DEAD (26.9 g, 154.5 mmol)at 0° C. under N₂ for 30 min. The mixture was stirred for another 1.5hour at 0° C. under N₂. The mixture was quenched with H₂O (300 mL) at 0°C., and extracted with EA (400 mL×3). The organic layer was concentratedto give a residue, which was purified by column chromatography on silicagel eluting with PE:EA=5:1 to PE:EA=4:1 to give crude product. The crudeproduct was further purified by column chromatography on silica geleluting with DCM to give 3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (26.8 g, 55% yield) as a pale yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 7.32-7.29 (d, J=8.8 Hz, 2H), 6.83-6.81 (d, J=8.8 Hz,2H), 4.96-4.83 (dd, J=13.6 Hz, J=38 Hz, 2H), 4.72-4.70 (m, 1H), 3.78 (s,3H), 3.06-2.99 (m, 1H), 2.76-2.72 (m, 1H), 2.36-2.32 (m, 1H), 2.25-2.21(m, 1H).

5-Chloro-1-methyl-N-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidin-7-amine(Intermediate LK)

Step 1—Methyl 2-methyl-4-nitro-pyrazole-3-carboxylate

To a mixture of methyl 4-nitro-1H-pyrazole-5-carboxylate (30.0 g, 175mmol, Intermediate HL) and K₂CO₃ (48.4 g, 350 mmol) in acetone (600 mL)was added MeI (49.7 g, 350 mmol, 21.8 mL). The reaction mixture wasstirred at 70° C. for 2 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (10.0 g, 30% yield) as lightyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 4.01 (s, 3H), 4.01(s, 3H).

Step 2—2-Methyl-4-nitro-pyrazole-3-carboxamide

To a mixture of methyl 2-methyl-4-nitro-pyrazole-3-carboxylate (10.0 g,54.0 mmol) in THF (20 mL) was added NH₃H₂O (27.3 g, 740 mmol, 30 mL,95%). The reaction mixture was stirred at 100° C. for 16 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (8.80 g, 95% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.46 (s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 3.86 (s, 3H).

Step 3—4-Amino-2-methyl-pyrazole-3-carboxamide

To a mixture of 2-methyl-4-nitro-pyrazole-3-carboxamide (8.80 g, 51.7mmol) in MeOH (100 mL) was added Pd/C (6.00 g, 10 wt %). The reactionmixture was stirred at rt for 12 hours under H₂ (15 psi) atmosphere. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (7.10 g, 97% yield) as red solid. ¹H NMR (400MHz, DMSO-d₆) δ 7.37 (s, 2H), 7.02 (s, 1H), 4.41 (s, 2H), 3.89 (s, 3H).

Step 4—1-Methylpyrazolo[4,3-d]pyrimidine-5,7-diol

To a mixture of 4-amino-2-methyl-pyrazole-3-carboxamide (11.3 g, 80.6mmol) in DMF (120 mL) was added CDI (26.1 g, 161 mmol). The reactionmixture was stirred at 90° C. for 24 hours. On completion, the reactionmixture was diluted with water (400 mL) then the solid was formed, andfiltered to afford solid. The solid was washed with water (1 L) to givethe title compound (13.0 g, 97% yield) as off-white solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.08 (s, 1H), 10.92 (s, 1H), 7.33 (s, 1H), 4.04 (s,3H).

Step 5—5,7-Dichloro-1-methyl-pyrazolo[4,3-d]pyrimidine

To a mixture of 1-methylpyrazolo[4,3-d]pyrimidine-5,7-diol (5.00 g, 30.1mmol) in POCl₃ (50.0 g, 326 mmol, 30.3 mL) was added N,N-diethylaniline(4.46 g, 29.8 mmol, 4.78 mL). The reaction mixture was stirred at 110°C. for 4 hours. On completion, the reaction mixture was concentrated invacuo. The residue was purified by column chromatography to give thetitle compound (3.70 g, 60% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.48 (s, 1H), 4.33 (s, 3H).

Step6—5-Chloro-1-methyl-N-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidin-7-amine

To a solution of 5,7-dichloro-1-methyl-pyrazolo[4,3-d]pyrimidine (1.00g, 4.93 mmol) and 4-morpholinocyclohexanamine (1.27 g, 4.93 mmol, 2HCl,CAS #558442-97-0) in ACN (30 mL) was added Na₂CO₃ (2.09 g, 19.70 mmol).The reaction mixture was stirred at 80° C. for 12 hours. The reactionmixture was concentrated in vacuo, diluted with DCM (30 mL), andfiltered. The filtrate was concentrated in vacuo. The crude product wastriturated with ACN/DCM/PE=1:0.2:10 (30 mL) to give the title compound(1.30 g, 75% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.85(s, 1H), 5.18 (d, J=6.8 Hz, 1H), 4.30 (s, 3H), 4.28-4.17 (m, 1H), 3.86(s, 4H), 2.74 (s, 4H), 2.56-2.50 (m, 1H), 2.36 (d, J=11.6 Hz, 2H), 2.13(d, J=11.6 Hz, 2H), 1.69-1.53 (m, 2H), 1.47-1.32 (m, 2H).

Tert-butylN-[2-[2-[2-[2-[2-(4-aminopyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(Intermediate LL)

Step 1—Tert-ButylN-[2-[2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (1.76 g, 4.24 mmol, synthesized via Step 1 ofIntermediate HH) and 4-nitro-1H-pyrazole (0.40 g, 3.54 mmol, CAS#2075-46-9) in DMF (15 mL) was added Cs₂CO₃ (2.31 g, 7.07 mmol). Thereaction mixture was stirred at 130° C. for 3 hours. On completion, themixture was diluted with H₂O (50 mL), then extracted with EA (2×100 mL).The combined organic phase was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(1.20 g, 78% yield) as yellow oil. LC-MS (ESI⁺) m/z 455.2 (M+Na)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[2-[2-(4-aminopyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (1.20 g, 2.77 mmol) in MeOH (20 mL) was added Pd/C (800mg, 10 wt %). The reaction mixture was stirred at rt for 12 hours underH₂ (15 Psi) atmosphere. On completion, the reaction mixture was filteredand concentrated in vacuo to give the title compound (1.00 g, 89% yield)as red oil. ¹H NMR (400 MHz, CDCl₃) δ 7.16 (d, J=5.2 Hz, 2H), 5.23 (s,1H), 4.17 (t, J=5.2 Hz, 2H), 3.78 (t, J=5.2 Hz, 2H), 3.65-3.51 (m, 14H),3.30 (d, J=4.8 Hz, 2H), 2.67 (s, 2H), 1.43 (s, 9H).

1-[2-[2-[2-(4-Aminopyrazol-1-yl)ethoxy]ethoxy]ethoxy]pentan-2-one(Intermediate LM)

Step 1—Ethyl2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]acetate

To a mixture of ethyl2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (0.5 g, 1.59mmol, Intermediate BI) and 4-nitro-1H-pyrazole (270 mg, 2.38 mmol) inDMF (10 mL) was added Cs₂CO₃ (1.04 g, 3.18 mmol). The reaction mixturewas stirred at rt for 24 hours under N₂ atmosphere. On completion, thereaction mixture was diluted with H₂O (20 mL) and extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (50 ml),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash silica gel chromatography to give the title compound(0.5 g, 1.43 mmol, 90% yield, 95% purity) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ=8.84 (s, 1H), 8.27 (s, 1H), 4.35 (t, J=5.2 Hz, 2H),4.19-4.04 (m, 4H), 3.82 (t, J=5.2 Hz, 2H), 3.62-3.46 (m, 8H), 1.19 (t,J=7.2 Hz, 3H) LC-MS (ESI⁺) m/z 332.2 (M+H)⁺.

Step 2—1-[2-[2-[2-(4-Aminopyrazol-1-yl)ethoxy]ethoxy]ethoxy]pentan-2-one

To a solution of ethyl2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]acetate (0.5 g,1.51 mmol) in EtOH (10 mL) was added Pd/C (0.05 g, 50 wt %) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H2 (15 psi) at rt for 2 hours. Oncompletion, the mixture was filtered with celite. The filtrate wasconcentrated in vacuo to give the title compound (0.34 g, 75% yield) asblack red oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.14-7.01 (m, 1H), 6.96-6.83(m, 1H), 4.17-4.09 (m, 4H), 4.08-4.03 (m, 2H), 3.72-3.66 (m, 2H),3.63-3.57 (m, 2H), 3.55-3.51 (m, 2H), 3.49 (s, 4H), 1.25-1.17 (m, 3H).

3-[4-[4-(4-aminobutoxy)butyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate LN)

Step 1—Tert-ButylN-[4-([4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]but-3-yn-1-yl]oxy)butyl]carbamate

To a stirred mixture of3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(1.5 g, 4.4 mmol, Intermediate HP), Pd(PPh₃)₂Cl₂ (311.3 mg, 0.44 mmol)and CuI (84.5 mg, 0.44 mmol) in DMA (22 mL) and TEA (7 mL) was addedtert-butyl N-[4-(but-3-yn-1-yloxy)butyl]carbamate (5.4 g, 22.2 mmol,Intermediate OI) at rt under nitrogen atmosphere. The resulting mixturewas purged with nitrogen three times and stirred for 16 h at 85° C.under nitrogen atmosphere. The resulting mixture was cooled andconcentrated under reduced pressure to remove TEA. The resulting mixturewas diluted with a solution of AcOH (3 mL) in ice water (50 mL). Theresulting mixture was extracted with EtOAc (2×50 mL). The combinedorganic layers was washed with brine (30 mL) and dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure. The residue was purified by reverse phase flash chromatographywith the following conditions: Column: WelFlash™ C18-1, 20-40 m, 120 g;Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 50%-60% Bin 20 min; Flow rate: 60 mL/min; Detector: 220/254 nm; desired fractionswere collected at 57% B and concentrated under reduced pressure toafford tert-butylN-[4-([4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]but-3-yn-1-yl]oxy)butyl]carbamate(1.4 g, 63%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11(s, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 7.00 (d, J=7.8Hz, 1H), 6.79 (t, J=5.7 Hz, 1H), 5.39 (dd, J=12.6, 5.4 Hz, 1H), 3.65 (s,3H), 3.63-3.54 (m, 2H), 3.43 (t, J=6.3 Hz, 2H), 2.98-2.83 (m, 3H),2.79-2.58 (m, 4H), 2.03 (dt, J=10.8, 5.1 Hz, 1H), 1.56-1.39 (m, 4H),1.37 (s, 9H); LC/MS (ESI, m/z): [(M−1)]⁻=497.15.

Step 2—Tert-ButylN-(4-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]butoxy]butyl)carbamate

To a stirred solution of tert-butylN-[4-([4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]but-3-yn-1-yl]oxy)butyl]carbamate(800 mg, 1.60 mmol) in THF (20 mL) was added palladium on charcoal (80mg, 10% w/w) at room temperature. The resulting mixture was stirred for3 h at rt under hydrogen atmosphere. After filtration, the filter cakewas washed with EtOAc (2×10 mL). The filtrate was concentrated underreduced pressure to afford tert-butylN-(4-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]butoxy]butyl)carbamate(500 mg, 62%) as a white solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s,1H), 6.96 (d, J=5.0 Hz, 2H), 6.87 (q, J=4.6 Hz, 1H), 6.77 (t, J=6.2 Hz,1H), 5.37 (dd, J=12.5, 5.4 Hz, 1H), 3.56 (s, 3H), 3.40 (t, J=5.8 Hz,2H), 3.37-3.29 (m, 2H), 3.00-2.82 (m, 5H), 2.78-2.57 (m, 2H), 2.06-1.95(m, 1H), 1.71-1.55 (m, 4H), 1.53-1.37 (m, 4H), 1.37 (s, 9H); LC/MS (ESI,m/z): [(M+1)]⁺=503.20.

Step3—3-[4-[4-(4-Aminobutoxy)butyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride

To a stirred solution of tert-butylN-(4-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]butoxy]butyl)carbamate(500 mg, 0.99 mmol) in dioxane (4 mL) was added a solution ofhydrochloride in 1,4-dioxane (4 M, 4 mL) dropwise at rt under nitrogenatmosphere. The resulting solution was stirred for 2 h at rt undernitrogen atmosphere. The resulting mixture was concentrated underreduced pressure to afford3-[4-[4-(4-aminobutoxy)butyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride (420 mg, 96%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.08 (s, 1H), 7.88 (br s, 3H), 7.02-6.92 (m, 2H), 6.87 (dd, J=6.2,2.6 Hz, 1H), 5.38 (dd, J=12.6, 5.4 Hz, 1H), 3.57 (s, 3H), 3.47-3.28 (m,4H), 2.99-2.84 (m, 3H), 2.79-2.58 (m, 4H), 2.00 (dt, J=11.1, 5.2 Hz,1H), 1.69-1.50 (m, 8H); LC/MS (ESI, m/z): [(M+1)]⁺=403.25.

(2S,4R)-1-[(2S)-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Intermediate LO)

Step 1—Tert-ButylN-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(250 mg, 535 umol, HCl, Intermediate CI) and2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetic acid(164 mg, 535 umol, CAS #462100-06-7) in DMF (5 mL) was added DIPEA (207mg, 1.61 mmol) and HATU (244 mg, 642 umol). The mixture was stirred atrt for 1 hour. On completion, the reaction mixture was quenched withwater 20 mL, and then extracted with EA (3×30 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by prep-HPLC (FA condition) togive the title compound (300 mg, 77% yield) as brown solid. LC-MS (ESI⁺)m/z 720.4 (M+H)⁺.

Step2—(2S,4R)-1-[(2S)-2-[[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a solution of tert-butylN-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]carbamate(240 mg, 333 umol) in DCM (12 mL) was added HCl/dioxane (4 M, 2.5 mL).The mixture was stirred at rt for 0.5 hour. On completion, the reactionmixture was concentrated in vacuo to give the title compound (0.21 g,96% yield, HCl) as light yellow solid. LC-MS (ESI⁺) m/z 620.2 (M+H)⁺.

(2S,4R)-1-[(2S)-2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Intermediate LP)

Step 1—Tert-ButylN-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (500 mg, 1.72mmol, Intermediate JX),(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (801 mg, 1.72 mmol,HCl, Intermediate CI), and TEA (174 mg, 1.72 mmol) in THF (20 mL) wasadded AcOH (103 mg, 1.72 mmol) and NaBH(OAc)₃ (727 mg, 3.43 mmol). Thenthe mixture was stirred at rt for 72 hrs under N₂ atmosphere. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was purified by Pre-HPLC (acid condition) to give the titlecompound (480 mg, 38% yield) as colorless solid. LC-MS (ESI⁺) m/z 706.5(M+H)⁺.

Step2—(2S,4R)-1-[(2S)-2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a solution of tert-butylN-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate(380 mg, 538 umol) in THF (10 mL) was added HCl/dioxane (4 M, 12 mL).The mixture was stirred at rt for 6 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (325 mg, 94% yield) aswhite solid. LC-MS (ESI⁺) m/z 606.4 (M+H)⁺.

Tert-Butyl N-[3-[3-(3-aminopropoxy)propoxy]propyl]carbamate(Intermediate LO)

Step 1—3-[3-(2-Cyanoethoxy)propoxy]propanenitrile

NaOMe (71.00 mg, 1.31 mmol) was dissolved in a solution of propane-1,3-diol (10 g, 131 mmol, CAS #126-30-7). Then prop-2-enenitrile (27.9 g,525 mmol, CAS #107-13-1) was added into the mixture. The reactionmixture was stirred at rt for 48 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by column chromatographyto give the title compound (21.6 g, 90% yield) as a brown solid. ¹H NMR(400 MHz, DMSO-d₆) δ 3.57 (t, J=6.4 Hz, 4H), 3.50 (t, J=6.4 Hz, 4H),2.74 (t, J=6.4 Hz, 4H), 1.79-1.73 (m, 2H).

Step 2—3-[3-(3-Aminopropoxy)propoxy]propan-1-amine

To a mixture of 3-[3-(2-cyanoethoxy)propoxy]propanenitrile (10 g, 54.9mmol) in MeOH (10 mL) was added Raney-Ni (9.40 g, 109 mmol), and thereaction mixture was stirred at 25° C. for 12 hrs under H₂ (50 psi). Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by column chromatography to give the title compound (8.40 g,80% yield) as brown oil. ¹H NMR (400 MHz, CDCl₃) δ 3.74-3.30 (m, 9H),2.79-2.38 (m, 4H), 1.85-1.56 (m, 4H), 1.91-1.48 (m, 1H).

Step 3—Tert-Butyl N-[3-[3-(3-aminopropoxy)propoxy]propyl]carbamate

To a solution of 3-[3-(3-aminopropoxy)propoxy]propan-1-amine (4.00 g,21.0 mmol) in DCM (40 mL) was dropwise added (Boc)₂O (5.51 g, 25.2mmol). The reaction mixture was stirred at rt for 12 hrs. On completion,the mixture was concentrated in vacuo. The residue was purified bycolumn chromatography to give the title compound (2.20 g, 36% yield)brown oil. ¹H NMR (400 MHz, CDCl₃) δ 3.66-3.60 (m, 3H), 3.66-3.60 (m,3H), 3.49-3.45 (m, 4H), 2.61-2.53 (m, 4H), 1.88-1.68 (m, 6H), 1.41 (s,9H).

4-[3-[3-(3-Aminopropoxy)propoxy]propylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate LR)

Step 1—Tert-ButylN-[3-[3-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propoxy]propoxy]propyl]carbamate

To a mixture of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione(476 mg, 1.72 mmol, Intermediate R), tert-butylN-[3-[3-(3-aminopropoxy)propoxy]propyl]carbamate (500 mg, 1.72 mmol,Intermediate LQ) in dioxane (10 mL) was added DIPEA (2.23 g, 17.2 mmol).The reaction mixture was stirred at 115° C. for 12 hrs. On completion,the mixture was concentrated in vacuo. The residue was purified byreverse phase (0.1% FA) to give the title compound (820 mg, 87% yield)as brown oil. LC-MS (ESI⁺) m/z 547.4 (M+H)⁺.

Step2—4-[3-[3-(3-Aminopropoxy)propoxy]propylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[3-[3-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propoxy]propoxy]propyl]carbamate (820 mg, 1.50 mmol) in DCM (5 mL) wasadded HCl/dioxane (4 M, 750 uL) and the reaction was stirred at rt for 1hr. On completion, the mixture was concentrated in vacuo to give thetitle compound (695 mg, 96% yield, HCl) as yellow oil. LC-MS (ESI⁺) m/z447.1 (M+H)⁺.

Tert-ButylN-[4-[4-[(3-formyl-1-methyl-pyrazol-4-yl)carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate LS)

Step 1—Isopropoxycarbonyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylate

To a solution of4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylicacid (3 g, 5.88 mmol, Intermediate KR) in THF (50 mL) was added TEA (595mg, 5.88 mmol). Then, the reaction mixture was cooled to −10° C. To themixture was added isopropyl carbonochloridate (1.44 g, 11.8 mmol). Theresulting reaction mixture was stirred at −10° C. for 2 hours. Oncompletion, the reaction mixture was filtered. The filtrate wasconcentrated in vacuo to give the title compound (3.51 g, 82% yield) asa white solid. LC-MS (ESI⁺) m/z 597.1 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-(hydroxymethyl)-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of isopropoxycarbonyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylate(3.51 g, 4.83 mmol) in THF (60 mL) was added LiBH₄ (315 mg, 14.5 mmol)and H₂O (1.37 g, 76.0 mmol). The reaction mixture was stirred at 0° C.for 1 hr. On completion, the reaction mixture was quenched with water (5mL) and the mixture was extracted with DCM (3×50 mL). The combinedorganic layer was washed with brine (20 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo to give the title compound(2.92 g, 73% yield) as a white solid. LC-MS (ESI⁺) m/z 497.1 (M+H)⁺.

Step 3—Tert-ButylN-[4-[4-[(3-formyl-1-methyl-pyrazol-4-yl)carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-(hydroxymethyl)-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(2.42 g, 4.19 mmol) in DCM (30 mL) was added DMP (3.56 g, 8.38 mmol).The reaction mixture was stirred at rt for 5 hrs. On completion, thereaction mixture was quenched with saturated Na₂S₂O₃ (20 mL), andextracted with DCM (3×30 mL). The combined organic layer was washed withsaturated NaHCO₃ (2×20 mL) and brine (30 mL), dried over with anhydroussodium sulfate, filtered and concentrated in vacuo. The residue wastriturated with methanol (10 mL) to give the title compound (1.60 g, 77%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1), 10.00(s, 1), 9.11 (s, 1), 8.67 (d, J=5.2 Hz, 1), 8.44 (s, 1H), 8.29 (s, 1H),7.79 (dd, J=1.2, 5.2 Hz, 1H), 4.91 (q, J=8.8 Hz, 2H), 4.02 (s, 3H), 1.54(s, 9H). LC-MS (ESI⁺) m/z 495.1 (M+H)⁺.

2-(2-Chloro-3-pyridyl)oxazole-4-carboxylic acid (Intermediate LT)

Step 1—Methyl 2-(2-chloro-3-pyridyl)oxazole-4-carboxylate

To a solution of methyl 2-amino-3-hydroxy-propanoate; hydrochloride(1.10 g, 7.06 mmol, CAS #2104-89-4) in DMA (20 mL) was added NaHCO₃(1.19 g, 14.1 mmol). The mixture was stirred at rt for 2 hours. Then, tothe mixture was added 2-chloropyridine-3-carbaldehyde (1 g, 7.06 mmol,CAS #36404-88-3) in one portion. The mixture was stirred for 12 hours.Then, to the mixture was added bromo(trichloro)methane (4.20 g, 21.2mmol) and DBU (3.23 g, 21.2 mmol) at 0° C. Then, the mixture was stirredat rt for an additional 12 hours. On completion, the mixture wasquenched with water (20 mL) and extracted with EA (2×100 mL). Theorganic layer was washed with brine (30 mL) and concentrated in vacuo.The residue was purified by silica gel chromatography (SiO₂) to give thetitle compound (1.2 g, 71% yield) as a white solid. LC-MS (ESI⁺) m/z238.9 (M+H)⁺.

Step 2—2-(2-Chloro-3-pyridyl)oxazole-4-carboxylic Acid

To a solution of methyl 2-(2-chloro-3-pyridyl) oxazole-4-carboxylate(1.2 g, 5.03 mmol) in a mixed solvent of H₂O (4 mL) and THF (20 mL) wasadded LiOH·H₂O (602 mg, 25.1 mmol). The mixture was stirred at rt for 5hours. On completion, the mixture was adjusted to pH=7 with 1N aq.HCl,and filtered. The filter cake was dried in vacuo to give the titlecompound (0.7 g, 62% yield) as a white solid. LC-MS (ESI⁺) m/z 225.0(M+H)⁺.

3-(Difluoromethyl)-1-methyl-pyrazol-4-amine (Intermediate LU)

Step 1—3-Difluoromethyl)-1-methyl-4-nitro-pyrazole

A mixture of 3-(difluoromethyl)-4-nitro-1H-pyrazole (1 g, 6.13 mmol,Intermediate HS), K₂CO₃ (1.69 g, 12.3 mmol), and MeI (1.74 g, 12.3 mmol)in acetone (20 mL) was degassed and purged with N₂ gas 3 times. Then themixture was stirred at 70° C. for 2 hours under N₂ atmosphere. Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo. The residue was purified by silica gel chromatography (SiO₂)to give the title compound (0.5 g, 46% yield) as yellow oil.

Step 2—3-(Difluoromethyl)-1-methyl-pyrazol-4-amine

To a solution of 3-(difluoromethyl)-1-methyl-4-nitro-pyrazole (200 mg,1.13 mmol) in MeOH (10 mL) was added Pd/C (200 mg, 10 wt %). The mixturewas stirred at rt for 3 hours under H₂ atmosphere (15 Psi). Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo to give the title compound (0.2 g, crude) as red oil. ¹H NMR(400 MHz, CDCl₃) δ 6.89 (s, 1H), 6.76-6.45 (m, 1H), 3.72 (s, 3H), 2.86(s, 2H).

2-(2-Chloro-3-pyridyl)-N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]oxazole-4-carboxamide(Intermediate LV)

A mixture of 3-(difluoromethyl)-1-methyl-pyrazol-4-amine (350 mg, 2.38mmol, Intermediate LU), 2-(2-chloro-3-pyridyl)oxazole-4-carboxylic acid(534 mg, 2.38 mmol, Intermediate LT), DIPEA (922 mg, 7.14 mmol), andHATU (1.09 g, 2.85 mmol) in DMF (3 mL) was degassed and purged with N₂gas 3 times, and then the mixture was stirred at rt for 3 hours under N₂atmosphere. On completion, the mixture was quenched with water (20 ml)and extracted with EA (2×20 mL). The organic layer was washed with brine(20 mL), then concentrated in vacuo to give the title compound (0.6 g,96% yield) as a white solid. LC-MS (ESI⁺) m/z 354.1 (M+H)⁺.

2-[2-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethylamino]-3-pyridyl]-N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]oxazole-4-carboxamide(Intermediate LW)

Step 1—Tert-ButylN-[2-[2-[2-[2-[[3-[4-[[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2-chloro-3-pyridyl)-N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]oxazole-4-carboxamide(200 mg, 565 umol, Intermediate LV) in NMP (2 mL) was added tert-butylN-[2-[2-[2-(2-aminoethoxy) ethoxy]ethoxy]ethyl]carbamate (827 mg, 2.83mmol, CAS #101187-40-0). The mixture was stirred at 150° C. for 1 hourunder microwave. On completion, the mixture was concentrated in vacuo.The residue was purified by prep-HPLC (acid condition) to give the titlecompound (0.2 g, 55% yield) as a white solid. LC-MS (ESI⁺) m/z 610.4(M+H)⁺.

Step2—2-[2-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethylamino]-3-pyridyl]-N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butylN-[2-[2-[2-[2-[[3-[4-[[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]carbamoyl] oxazol-2-yl]-2-pyridyl]amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate (200 mg, 328 umol) in THF (5mL) was added HCl/dioxane (4 M, 4 mL). The mixture was stirred at rt for16 hours. On completion, the mixture was concentrated in vacuo to givethe title compound (180 mg, 93% yield, HCl) as a yellow solid. LC-MS(ESI⁺) m/z 510.3 (M+H)⁺.

7-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-[(2S)-2-[(2-methoxyacetyl)amino]-3,3-dimethyl-butanoyl]-N-[(1R)-tetralin-1-yl]-3,4-dihydro-1H-isoquinoline-3-carboxamide(Intermediate LX)

7-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-2-[(2S)-2-[(2-methoxyacetyl)amino]-3,3-dimethyl-butanoyl]-N-[(1R)-tetralin-1-yl]-3,4-dihydro-1H-isoquinoline-3-carboxamidewas synthesized as described for Intermediate LY, using2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl4-methylbenzenesulfonate,Intermediate ON, as the tosylate in Step 1 to couple with alcoholIntermediate MH. ¹H NMR (400 MHz, DMSO-d₆) δ 8.21-8.15 (m, 1H),7.45-7.30 (m, 1H), 7.14-6.77 (m, 7H), 5.11-4.40 (m, 5H), 4.07-4.02 (m,2H), 3.90-3.72 (m, 4H), 3.60-3.41 (m, 12H), 3.36-3.20 (m, 7H), 3.05-2.93(m, 2H), 2.76-2.61 (m, 4H), 1.87-1.52 (m, 4H), 1.03-0.93 (m, 9H). LC-MS(ESI⁺): m/z 727.2 (M+H)⁺

7-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-2-[(2S)-2-[(2-methoxyacetyl)amino]-3,3-dimethyl-butanoyl]-N-[(1R)-tetralin-1-yl]-3,4-dihydro-1H-isoquinoline-3-carboxamide(Intermediate LY)

Step 1—Tert-Butyl(2-(2-(2-(2-(((S)-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

To a mixture of(S)-7-hydroxy-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide(1.75 g, 3.45 mmol, Intermediate MH) and2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl 4-methylbenzenesulfonate (1.7 g, 3.8 mmol, Intermediate LD) in DMF (25 mL) wasadded K₂CO₃ (714 mg, 5.2 mmol), and the mixture was stirred at 110° C.for overnight. The solution was then poured into water (150 mL) and themixture was extracted with EtOAc (20 mL×2). The combined organic layerwas washed with brine (50 mL×3), dried over Na₂SO₄, filtered,concentrated in vacuo and purified via column chromatography (Petroleumether/EtOAc=1/1) to give the title compound (1.38 g, 51.1% yield) as acolorless oil. LC-MS (ESI⁺): m/z 683.2 (M−99)⁺.

Step2—(S)-7-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

To a mixture of tert-butyl(2-(2-(2-(2-(((S)-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)oxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate(1.38 g, 1.76 mmol) in THF (15 mL) was added 4 M HCl/dioxane (10 mL),and the mixture was stirred at rt for overnight. Then the solution waspoured into aq.NaHCO₃ (100 mL), and the mixture was extracted with EtOAc(20 mL×2). The combined organic layer was washed with brine (50 mL×3),dried over Na₂SO₄, filtered, concentrated in vacuo and purified viacolumn chromatography (DCM/MeOH=10/1) to give the title compound (600mg, 50% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (s, 1H),8.23-8.17 (m, 1H), 7.46-7.30 (m, 1H), 7.14-6.77 (m, 7H), 5.12-4.41 (m,5H), 4.07-4.03 (m, 2H), 3.90-3.73 (m, 4H), 3.60-3.47 (m, 10H), 3.32-3.29(m, 3H), 3.06-2.93 (m, 2H), 2.81-2.64 (m, 4H), 1.87-1.52 (m, 4H),1.03-0.94 (m, 9H). LC-MS (ESI⁺): m/z 683.2 (M+H)⁺.

3-[4-[3-[3-(3-aminopropoxy)-2,2-dimethyl-propoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate LZ)

Step 1—Tert-ButylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)-2,2-dimethylpropoxy]propyl]carbamate

To a stirred solution of3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(2.45 g, 7.25 mmol, Intermediate HP) and tert-butylN-[3-[2,2-dimethyl-3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (1.5 g,4.85 mmol, Intermediate OG) in DMA (25 mL) were added CuI (138.0 mg,0.72 mmol), TEA (10 mL) and Pd(PPh₃)₄ (837.2 mg, 0.72 mmol) at rt undernitrogen atmosphere. The resulting mixture was stirred for 5 h at 90° C.under nitrogen atmosphere. The resulting mixture was cooled andconcentrated under reduced pressure to remove TEA. The residue waspurified by reverse phase flash chromatography with the followingconditions: Column: WelFlash™ C18-1, 20-40 m, 300 g; Eluent A: Water(plus 10 mmol/L FA); Eluent B: ACN; Gradient: 48%-68% B in 25 min; Flowrate: 80 mL/min; Detector: 220/254 nm; desired fractions were collectedat 60% B and concentrated under reduced pressure to afford tert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)-2,2-dimethylpropoxy]propyl]carbamate(1.4 g, 33%) as a light brown solid: ¹H NMR (400 MHz, DMSO-d₆) δ 11.12(s, 1H), 7.20-7.16 (m, 1H), 7.12 (dd, J=8.0, 1.1 Hz, 1H), 7.03 (t, J=7.9Hz, 1H), 6.71 (s, 1H), 5.41 (dd, J=12.6, 5.4 Hz, 1H), 4.44 (s, 2H), 3.65(s, 3H), 3.36 (t, J=6.2 Hz, 2H), 3.32-3.30 (m, 2H), 3.13 (s, 2H), 2.97(q, J=6.6 Hz, 2H), 2.94-2.84 (m, 1H), 2.79-2.58 (m, 2H), 2.09-1.99 (m,1H), 1.59 (p, J=6.5 Hz, 2H), 1.36 (s, 9H), 0.88 (s, 6H); LC/MS (ESI,m/z): [(M−100±1)]⁺=457.4.

Step2—3-(4-[3-[3-(3-Aminopropoxy)-2,2-dimethylpropoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride

To a solution of tert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)-2,2-dimethylpropoxy]propyl]carbamate(800 mg, 1.44 mmol) in THF (15 mL) was added palladium on charcoal(152.9 mg, 10% w/w) in a pressure tank. The mixture was purged withhydrogen gas 3 times at rt and the mixture was hydrogenated at rt under1 psi for 16 h. After filtration, the filter cake was concentrated underreduced pressure. The residue was dissolved in dioxane (8 mL). To it wasadded a solution of HCl in 1,4-dioxane (4 M, 8 mL) dropwise at rt undernitrogen atmosphere. The resulting solution was stirred for 2 hours atrt under nitrogen atmosphere. The resulting solution was concentratedunder reduced pressure. The residue was purified by reverse phase flashchromatography with the following conditions: Column: WelFlash™ C18-1,20-40 μm, 80 g; Eluent A: Water (plus 10 mmol/L FA); Eluent B: ACN;Gradient: 45%-70% B in 25 min; Flow rate: 50 mL/min; Detector: 220/254nm; desired fractions were collected at 63% B and concentrated underreduced pressure to afford3-(4-[3-[3-(3-aminopropoxy)-2,2-dimethylpropoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride (72.8 mg, 10%) as a light yellow solid: ¹H NMR (400 MHz,CDCl₃) δ 8.51 (br s, 1H), 7.48 (br s, 3H), 6.99 (t, J=7.8 Hz, 1H), 6.90(d, J=7.8 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 5.22 (dd, J=12.4, 5.5 Hz,1H), 3.69 (s, 3H), 3.51-3.38 (m, 4H), 3.20-3.08 (m, 4H), 3.06-2.93 (m,4H), 2.89-2.66 (m, 3H), 2.22-2.13 (m, 1H), 1.99-1.83 (m, 4H), 0.87 (s,6H); LC/MS (ESI, m/z): [(M+1)]⁺=461.35.

3-[5-[3-[3-(3-aminopropoxy)-2,2-dimethyl-propoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate MA)

Step 1—Tert-ButylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)-2,2-dimethylpropoxy]propyl]carbamate

To a stirred solution of3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(1.68 g, 4.97 mmol, Intermediate HN) and tert-butylN-[3-[2,2-dimethyl-3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (996.6mg, 3.33 mmol, Intermediate OG) in DMA (15 mL) were added CuI (94.6 mg,0.50 mmol), TEA (10 mL) and Pd(PPh₃)₄ (574.1 mg, 0.50 mmol) at roomtemperature under nitrogen atmosphere. The mixture was purged withnitrogen gas 3 times, and the resulting mixture was stirred for 5 h at90° C. under nitrogen atmosphere. After cooling to rt, the mixture waspurified by reverse phase flash chromatography with the followingconditions: Column: WelFlash™ C18-1, 20-40 m, 300 g; Eluent A: Water(plus 10 mmol/L FA); Eluent B: ACN; Gradient: 48%-68% B in 20 min; Flowrate: 80 mL/min; Detector: 220/254 nm; desired fractions were collectedat 60% B and concentrated under reduced pressure to afford tert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)-2,2-dimethylpropoxy]propyl]carbamate(600 mg, 22%) as a light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12(br s, 1H), 7.32 (d, J=1.4 Hz, 1H), 7.22-7.07 (m, 2H), 6.84-6.64 (m, 1),5.40 (dd, J=12.8, 5.4 Hz, 1), 4.37 (s, 2H), 3.40-3.32 (m, 5H), 3.29 (s,2H), 3.13 (s, 2H), 2.98 (q, J=6.6 Hz, 2H), 2.95-2.83 (m, 1H), 2.76-2.59(m, 2H), 2.04 (ddd, J=10.8, 6.0, 3.9 Hz, 1H), 1.61 (t, J=6.7 Hz, 2H),1.37 (s, 9H), 0.88 (s, 6H); LC/MS (ESI, m/z): [(M+1)]⁺=557.25.

Step2—3-(5-[3-[3-(3-Aminopropoxy)-2,2-dimethylpropoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride

To a solution of tert-butylN-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)-2,2-dimethylpropoxy]propyl]carbamate(600 mg, 1.08 mmol) in THF (10 mL) was added palladium on charcoal(114.7 mg, 10% w/w) in a pressure tank. The mixture was purged withhydrogen gas 3 times and was hydrogenated at rt under 1 psi of hydrogenfor 16 h. After filtration, the filtrate was concentrated under reducedpressure. The residue was dissolved in dioxane (5 mL). To it was added asolution of HCl in 1,4-dioxane (4 M, 5 mL) dropwise at rt under nitrogenatmosphere. The resulting solution was stirred for 2 hours at rt undernitrogen atmosphere, then was concentrated under reduced pressure. Theresidue was purified by reverse phase flash chromatography with thefollowing conditions: Column: WelFlash™ C18-I, 20-40 μm, 80 g; Eluent A:Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 45%-70% B in 25 min;Flow rate: 50 mL/min; Detector: 220/254 nm; desired fractions werecollected at 63% B and concentrated under reduced pressure to afford3-(5-[3-[3-(3-aminopropoxy)-2,2-dimethylpropoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dionehydrochloride (58.1 mg, 10%) as a light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.47 (s, 1H), 8.21 (br, 3H), 6.96-6.76 (m, 3H), 5.28 (dd,J=12.7, 5.4 Hz, 1H), 3.47-3.39 (m, 5H), 3.39-3.32 (m, 2H), 3.19-3.08 (m,4H), 2.96 (t, J=6.9 Hz, 2H), 2.88-2.79 (m, 2H), 2.72 (q, J=11.8, 9.5 Hz,3H), 2.22-2.12 (m, 1H), 1.87 (q, J=6.4, 5.6 Hz, 4H), 0.87 (s, 3H), 0.86(s, 3H); LC/MS (ESI, m/z): [(M+1)]+=461.40.

N-[3-carbamoyl-1-(4-formylphenvl)pyrazol-4-yl]oxazole-4-carboxamide(Intermediate MB)

Step1—N-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]oxazole-4-carboxamide

To a solution of4-amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxamide (200 mg, 861umol, Intermediate GB) and oxazole-4-carboxylic acid (97.3 mg, 861 umol,CAS #23012-13-7) in DMF (3 mL) was added DIPEA (333 mg, 2.58 mmol) andHATU (392 mg, 1.03 mmol). The mixture was stirred at rt for 0.5 hour. Oncompletion, the mixture was diluted with H₂O (15 mL), the mixture wasfiltered and the solid was dried in vacuo to give the title compound(270 mg, 75% yield) as white solid. LC-MS (ESI⁺) m/z 350.2 (M+Na)⁺.

Step2—N-[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]oxazole-4-carboxamide

To a solution ofN-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]oxazole-4-carboxamide(270 mg, 824 umol) in DCM (30 mL) was added DMP (419 mg, 989 umol). Themixture was stirred at rt for 2 hours. On completion, the mixture wasquenched with saturated aq. Na₂S₂O₃ (30 mL) and washed with saturatedaq. NaHCO₃ (2×30 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (100 mg,40% yield) as yellow solid. LC-MS (ESI⁺) m/z 326.1 (M+H)⁺.

1-Methyl-4-[[2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]pyrazole-3-carboxylicAcid (Intermediate MC)

To a solution of4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazole-3-carboxylicacid (35 mg, 68.6 umol, Intermediate KR) in DCM (2 mL) was added 4.0 MHCl/dioxane (2 mL). The reaction mixture was stirred at rt for 2 hours.On completion, the mixture was concentrated in vacuo to give the titlecompound (30 mg, 98% yield, HCl) as a yellow solid. LC-MS (ESI⁺) m/z411.5 (M+H)⁺.

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5yl)phenyl]methyl]pyrrolidine-2-carboxamide(Intermediate MD)

Step 1—Tert-Butyl((S)-22-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-23,23-dimethyl-20-oxo-3,6,9,12,15,18-hexaoxa-21-azatetracosyl)carbamate

To a solution of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(1.0 g, 2.15 mmol, Intermediate G) in DMF (100 mL) was added2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-oicacid (1.083 g, 2.47 mmol, Intermediate OF), HATU (939.1 mg, 2.47 mmol),and DIPEA (693.4 mg, 5.4 mmol) at rt. The reaction mixture was stirredrt for 1 h. The reaction mixture was diluted with water, then extractedwith EA (100 mL×2). The combined organic layer was washed with brine (50mL×3), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo.The residue was purified by column chromatography (DCM/MeOH=0%-10%) togive the desired compound (1.4 g, 76.5%) as a colorless oil. LC-MS(ESI⁺): m/z 852.6 (M+H)⁺.

Step2—(2S,4R)-1-((S)-23-amino-2-(tert-butyl)-4-oxo-6,9,12,15,18,21-hexaoxa-3-azatricosan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A solution of tert-butyl((S)-22-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-23,23-dimethyl-20-oxo-3,6,9,12,15,18-hexaoxa-21-azatetracosyl)carbamate(1.4 g, 1.65 mmol) in dioxane (4 N HCl in dioxane, 20 mL) was stirred rtfor 2 h. The reaction mixture was concentrated in vacuo and the residuewas purified via reverse phase column chromatography (H₂O (0.1% formicacid)/CH₃CN=0%-100%) to give the desired FA salt compound (545.1 g,43.99%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H),7.49-7.38 (m, 4H), 4.70 (s, 1H), 4.59-4.48 (m, 3H), 4.36 (dd, J=15.2,3.4 Hz, 1H), 4.09 (s, 2H), 3.83 (dt, J=11.0, 7.4 Hz, 2H), 3.74 (dd,J=6.4, 3.8 Hz, 2H), 3.72-3.60 (m, 20H), 3.13 (dd, J=6.4, 3.9 Hz, 2H),2.47 (s, 3H), 2.30-2.20 (m, 1H), 2.09 (ddd, J=13.3, 9.2, 4.4 Hz, 1H),1.05 (s, 9H). LC-MS (ESI⁺): m/z 752.4 (M+H)⁺.

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(Intermediate ME)

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamidewas synthesized as described for Intermediate MD, using2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-oic acid(Intermediate EN) as the acid which coupled with Intermediate G in thefirst step. ¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.61-8.58 (t,J=6.0 Hz, 1H), 7.79 (s, 3H), 7.51-7.38 (m, 5H), 4.58-4.55 (d, J=9.6 Hz,1H), 4.45-4.23 (m, 4H), 3.98 (s, 2H), 3.69-3.51 (m, 16H), 2.99-2.95 (m,2H), 2.44 (s, 3H), 2.09-2.04 (m, 1H), 1.93-1.87 (m, 1H), 0.95 (s, 9H).LC-MS (ESI⁺): m/z 664.2 (M+H)⁺.

1-Methyl-4-(oxazole-4-carbonylamino)pyrazole-3-carboxylic Acid(Intermediate MF)

Step 1—Methyl 1-methyl-4-(oxazole-4-carbonylamino)pyrazole-3-carboxylate

To a solution of methyl 4-amino-1-methyl-pyrazole-3-carboxylate (100 mg,645 umol, Intermediate KQ) and oxazole-4-carboxylic acid (72.9 mg, 645umol, CAS #23012-13-7) in DMF (2 mL) was added DIPEA (333 mg, 2.58 mmol)and HATU (294 mg, 773 umol). The reaction mixture was stirred at rt for0.5 hour. On completion, the mixture was quenched with water (30 mL),filtered and the filter cake was dried in vacuo to give the titlecompound (100 mg, 62% yield) as a white solid. LC-MS (ESI⁺) m/z 251.2(M+H)⁺.

Step 2—1-Methyl-4-(oxazole-4-carbonylamino)pyrazole-3-carboxylic Acid

To a solution of methyl 1-methyl-4-(oxazole-4-carbonylamino)pyrazole-3-carboxylate (100 mg, 400 umol) in a mixed solvent of THF (2mL), MeOH (1 mL) and H₂O (0.4 mL) was added LiOH (47.9 mg, 2.00 mmol).The reaction mixture was stirred at rt for 12 hours. On completion, themixture was acidified with 1N aq.HCl to pH=4-6, then stirred andfiltered. The filter cake was dried in vacuo to give the title compound(50 mg, 53% yield) as a white solid. LC-MS (ESI⁺) m/z 237.1 (M+H)⁺.

3-[4-(3-Aminopropyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate MG)

Step 1—Tert-ButylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]carbamate

To a mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (150mg, 444 umol, Intermediate HP), tert-butyl N-prop-2-ynylcarbamate (172mg, 1.11 mmol) in DMF (2.5 mL) was added TEA (808 mg, 7.98 mmol), CuI(25.3 mg, 133 umol), Pd(PPh₃)₂Cl₂ (93.4 mg, 133 umol) under N₂. Thereaction mixture was stirred at 80° C. for 12 hrs. On completion, thereaction mixture was poured into water (10 mL). The aqueous phase wasthen extracted with ethyl acetate (2×20 mL). The combined organic phasewas washed with brine (2×25 mL), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=3:1) to give thetitle compound (96 mg, 52% yield) as brown oil. LC-MS (ESI⁺) m/z 357.2(M−55)

Step 2—Tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]carbamate

To a solution of tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]carbamate (112 mg, 272 umol) in THF (5 mL) was added Pd/C(543 umol, 20 wt %) and Pd(OH)₂/C (543 umol, 20 wt %) under N₂. Thesuspension was degassed under vacuum and purged with H₂ gas 3 times. Themixture was stirred (15 Psi) at rt for 12 hours under H₂. On completion,the mixture was filtered and concentrated in vacuo to give the titlecompound (112 mg, 91% yield) as a white solid. LC-MS (ESI⁺) m/z 439.3(M+Na)⁺.

Step3—3-[4-(3-Aminopropyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]carbamate (112 mg, 269 umol) in DCM (5 mL) was added HCl/dioxane (4 M,134 uL). The mixture was stirred at rt for 1 hr. On completion, themixture was concentrated in vacuo to get the title compound (92 mg, 97%yield, HCl) as a white solid. LC-MS (ESI⁺) m/z 217.2 (M+Na)⁺.

(S)-7-hydroxy-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide(Intermediate MH)

Step1—(S)-7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylicAcid Hydrochloride

To concentrate HCl (780 mL) was added(S)-2-amino-3-(4-hydroxy-3,5-diiodophenyl)propanoic acid (65 g, 150mmol, CAS #18835-59-1), CH₂O (37% in H₂O) and DME (65 mL). The mixturewas heated to 72° C. slowly, and then stirred overnight. To the mixturewas added another 20 mL of CH₂O (37% in H₂O), and the reaction wasstirred for another 4 h at 72° C. The mixture was cooled to 0° C. andfiltered. The filter cake was washed with DME (50 mL) give(S)-7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid hydrochloride HCl salt (32 g, 72% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 9.69 (s, 1H), 7.73 (s, 1H), 4.34-4.30(dd, J=4.8 Hz, J=11.2 Hz, 1H), 4.14-4.00 (dd, J=16.4 Hz, J=40 Hz, 2H),3.24-3.18 (m, 1H), 3.09-3.02 (m, 1H). LC-MS (ESI⁺): m/z 482.5 (M+H)⁺.

Step2—(S)-2-(tert-butoxycarbonyl)-7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylicAcid

A mixture of(S)-7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid hydrochloride (20 g, 41.6 mmol 0, (Boc)₂O (13.6 g, 62.4 mmol), TEA(16.8 g, 166 mmol), H₂O (40 mL) and DMF (300 mL) was stirred overnightat rt. To the mixture was added H₂O (200 mL), and the solution waswashed with EA (200 mL). The aqueous layer adjusted with 1 N HCl topH<7, then extracted with EA (300 mL). The organic layer was washed withbrine (100 mL), dried over Na₂SO₄, filtered, concentrated, and purifiedby column to give(S)-2-(tert-butoxycarbonyl)-7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (15.5 g, 68% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.77 (s, 1), 9.46 (s, 1), 7.64 (s, 1), 4.83-4.67 (m, 1), 4.49-4.39 (m,1), 4.21-4.17 (d, J=16.8 Hz, 1H), 3.05-3.04 (d, J=4 Hz, 2H), 1.47-1.40(d, J=24.4 Hz, 9H).

Step 3:(S)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylicAcid

A mixture of(S)-2-(tert-butoxycarbonyl)-7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (7 g, 12.8 mmol), Pd/C (10 wt %, 1.4 g), TEA (2.9 g, 28.3 mmol) andMeOH (100 mL) was stirred for overnight at rt under N₂. The mixture wasfiltered to remove Pd/C, concentrated to dry, then H₂O (100 mL) wasadded and the mixture was washed with EA (100 mL). The aqueous layer wasadjusted with 1N HCl to pH<7, then extracted with EA (300 mL). Theorganic layer was dried over Na₂SO₄, filtered and concentrated to give(S)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (3 g, 80% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.58 (s, 1H), 9.26 (s, 1H), 6.97 (t, J=8.4 Hz, 1H), 6.58-6.52 (m, 2H),4.83-4.25 (m, 3H), 3.01-2.96 (m, 2H), 1.45-1.39 (d, J=26.4 Hz, 9H).LC-MS (ESI⁺): m/z 294.4 (M+H)⁺.

Step4—(S)-tert-butyl7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a mixture of(S)-2-(tert-butoxycarbonyl)-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid (32 g, 109 mmol) and (R)-1,2,3,4-tetrahydronaphthalen-1-amine (19.3g, 131 mmol, CAS #23357-46-2) in DMF (150 mL) was added HATU (54 g, 142mmol) and DIPEA (42 g, 328 mmol), and the mixture was stirred at rt for15 min. The solution was then poured into water (1500 mL) and extractedwith EtOAc (200 mL×2). The combined organic layer was washed with brine(500 mL×3), dried over Na₂SO₄, filtered, concentrated in vacuo andpurified via column chromatography (Petroleum ether/EtOAc=4/1) to givethe title compound (40.2 g, 86.9% yield) as a white solid. LC-MS (ESI⁺):m/z 423.1 (M+H)+

Step5—(S)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide hydrochloride

To a mixture of(S)-tert-butyl7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihy droisoquinoline-2(1H)-carboxylate (44 g, 104 mmol)in THF (300 mL) was added 4N HCl in dioxane (300 mL), and the mixturewas stirred at rt overnight. The solution was concentrated under reducedpressure to give the crude product, which was recrystallized by EA togive the title compound (33.3 g, 82.0% yield) as a white solid. LC-MS(ESI⁺): m/z 323.1 (M+H)⁺.

Step 6—Tert-Butyl((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate

To a mixture of(S)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamidehydrochloride(33.3 g, 92.8 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (22.5, 97.4 mmol, CAS#62963-35-9) in DMF (400 mL) was added HATU (42.3 g, 111.3 mmol) andDIPEA (48 g, 371 mmol), and the mixture was stirred at rt for 1.5 h. Thesolution was then poured into water (2500 mL) and the mixture wasextracted with EtOAc (200 mL×2). The combined organic layer was washedwith brine (500 mL×3), dried over Na₂SO₄, filtered, concentrated invacuo and purified via column chromatography (Petroleum ether/EtOAc=2/1)to give the title compound (21.5 g, 43.9% yield) as a white solid. LC-MS(ESI⁺): m/z 536.2 (M+H)⁺.

Step7—(S)-2-((S)-2-amino-3,3-dimethylbutanoyl)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamidehydrochloride

To a mixture of tert-butyl((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate(21.5 g, 40 mmol) in THF (200 mL) was added 4N HCl in dioxane (200 mL),and the mixture was stirred at rt overnight. The solution was thenpoured into aq.NaHCO₃ (1000 mL), and the mixture was extracted withEtOAc (200 mL×2). The combined organic layer was washed with brine (500mL×3), dried over Na₂SO₄, filtered, and concentrated in vacuo to givethe title compound as the HCl salt (17 g, 97% yield) as a white solid.LC-MS (ESI⁺): m/z 436.1 (M+H)⁺.

Step8—(S)-7-hydroxy-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

To a mixture of (S)-2-((S)-2-amino-3,3-dimethylbutanoyl)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamidehydrochloride (14.4 g, 33 mmol) and 2-methoxyacetic acid (2.97 g, 131mmol) in DMF (120 mL) was added HATU (15 g, 39.6 mmol) and DIPEA (6.4 g,49.5 mmol), and the mixture was stirred at rt for 1 h. The solution wasthen poured into water (1500 mL), and the mixture was extracted withEtOAc (200 mL×2). The combined organic layer was washed with brine (500mL×3), dried over Na₂SO₄, filtered, concentrated in vacuo and purifiedvia column chromatography (Petroleum ether/EtOAc=1/1) to give the titlecompound (14 g, 83.8% yield) as a white solid. LC-MS (ESI⁺): m/z 508.2(M+H)⁺.

1-methyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazole-3-carboxylicAcid (Intermediate MI)

Step 1—Methyl1-methyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazole-3-carboxylate

A mixture of methyl 4-amino-1-methyl-pyrazole-3-carboxylate (500 mg,3.22 mmol, Intermediate KQ), 2-(4-pyridyl)oxazole-4-carboxylic acid (612mg, 3.22 mmol, Intermediate ED), HATU (1.47 g, 3.87 mmol), and DIPEA(1.25 g, 9.67 mmol) in DMF (10 mL) was degassed and purged with N₂ gas 3times, and then the mixture was stirred at rt for 2 hours under N₂atmosphere. On completion, the mixture was quenched with water (50 mL),filtered and the filter cake was dried in vacuo to give the titlecompound (900 mg, 85% yield) as white solid. LC-MS (ESI⁺) m/z 328.2(M+H)⁺.

Step2—1-methyl-4-[[2-(4-pyridyl)oxazole-4-carbonyl]amino]pyrazole-3-carboxylicacid

To a solution of methyl 1-methyl-4-[[2-(4-pyridyl) oxazole-4-carbonyl]amino] pyrazole-3-carboxylate (900 mg, 2.75 mmol) in H₂O (4 mL) and THF(20 mL) was added LiOH (32 mg, 13.7 mmol). The mixture was stirred at rtfor 4 hours. On completion, the mixture was adjusted to pH=6 with 1Naq.HCl, filtered and the filter cake was dried in vacuo to give thetitle compound (600 mg, 69% yield) as white solid. LC-MS (ESI⁺) m/z314.1 (M+H)⁺.

[4-[(4-Tert-butoxycarbonylmorpholin-2-yl)ethoxymethyl]phenyl]boronicacid (Intermediate MJ)

Step 1—Tert-butyl2-[(4-bromophenyl)methoxymethyl]morpholine-4-carboxylate

To a mixture of 1-bromo-4-(bromomethyl)benzene (10.3 g, 41.4 mmol, CAS#3433-80-5), tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (4.50g, 20.7 mmol, CAS #135065-69-9), TBAI (0.80 g, 2.07 mmol) in DMF (80 mL)was added NaH (1.70 g, 41.4 mmol, 60% oil dispersion) at 0° C. Themixture was then stirred at rt for 12 hrs. On completion, the mixturewas concentrated in vacuo. The mixture was poured into a solution ofsaturated sodium bicarbonate (60 mL) and extracted with ethyl acetate(2×80 mL). The combined organic phase was washed with brine (2×80 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo at 45°C. The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=20:1) to give the title compound (4.80 g, 61% yield)as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J=8.4 Hz, 2H),7.23-7.18 (m, 1H), 7.21 (d, J=8.4 Hz, 1H), 4.51 (s, 2H), 3.90 (d, J=10.4Hz, 3H), 3.64-3.43 (m, 4H), 2.94 (s, 1H), 2.74 (s, 1H), 1.47 (s, 9H).

Step 2—Tert-Butyl2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxymethyl]morpholine-4-carboxylate

To a mixture of tert-butyl2-[(4-bromophenyl)methoxymethyl]morpholine-4-carboxylate (460 mg, 11.9mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(363 mg, 14.3 mmol) in dioxane (50 mL) was added Pd(dppf)Cl₂ (972 mg,1.19 mmol) and KOAc (234 mg, 23.8 mmol). The reaction mixture wasstirred at 100° C. for 12 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by column chromatographyto give the title compound (480 mg, 93% yield) as brown oil. ¹H NMR (400MHz, CDCl₃) δ 7.72 (d, J=7.8 Hz, 2H), 7.26 (d, J=7.8 Hz, 2H), 4.51 (s,2H), 3.83 (d, J=8.8 Hz, 3H), 3.52-3.36 (m, 4H), 2.86 (s, 1H), 2.66 (t,J=12.0 Hz, 1H), 1.39 (s, 9H), 1.27 (s, 12H).

Step3—[4-[(4-Tert-butoxvcarbonylmorpholin-2-yl)methoxymethyl]phenyl]boronicAcid

To a mixture of tert-butyl2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxymethyl]morpholine-4-carboxylate (4.80 g, 11.1 mmol) in THF (40 mL) and H₂O (8mL) was added NaIO₄ (7.10 g, 33.3 mmol). After that, to the reactionmixture was added 4M HCl (7.4 mL) and the mixture was stirred at rt for12 hrs. On completion, the mixture was concentrated in vacuo. Theresidue was purified by column chromatography to give the title compound(1.50 g, 38% yield) as brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s,2H), 7.77 (d, J=8.0 Hz, 2H), 7.28 (d, J=7.9 Hz, 2H), 4.50 (s, 2H),3.90-3.74 (m, 2H), 3.73-3.64 (m, 1H), 3.53-3.37 (m, 7H), 1.41 (s, 9H).

Tert-Butyl2-[[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]methoxymethyl]morpholine-4-carboxylate(Intermediate MK)

Step 1—Tert-Butyl2-[[4-(3-methoxycarbonyl-4-nitro-pyrazol-1-yl)phenyl]methoxymethyl]morpholine-4-carboxylate

To a mixture of methyl 4-nitro-1H-pyrazole-3-carboxylate (0.80 g, 4.70mmol, CAS #170487-38-4),[4-[(4-tert-butoxycarbonylmorpholin-2-yl)methoxymethyl]phenyl]boronicacid (1.50 g, 4.27 mmol, Intermediate MJ) in DCM (20 mL) was addedpyridine (1.35 g, 17.1 mmol) and Cu(OAc)₂ (1.16 g, 6.41 mmol) underoxygen, and the mixture was stirred at rt for 12 hrs. On completion, themixture was concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (1.10 g, 54% yield) as brownoil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s, 1H), 7.93 (s, 1H), 7.52 (s,1H), 7.10 (s, 1), 6.73 (d, J=8.4 Hz, 1H), 4.60-4.57 (m, 1H), 4.58 (s,1H), 4.35 (s, 1H), 4.03 (q, J=7.2 Hz, 1H), 3.95 (s, 3H), 3.82 (d, J=8.8Hz, 2H), 3.70 (d, J=12.4 Hz, 1H), 3.48-3.36 (m, 4H), 1.41 (s, 9H).

Step 2—Tert-Butyl2-[[4-(3-carbamoyl-4-nitro-pyrazol-1-yl)phenyl]methoxymethyl]morpholine-4-carboxylate

To a sealed tube was added a solution of tert-butyl2-[[4-(3-methoxycarbonyl-4-nitro-pyrazol-1-yl) phenyl]methoxymethyl]morpholine-4-carboxylate (1.10 g, 2.31 mmol), NH₃·H₂O (971mg, 6.93 mmol, 25% solution) in THF (10 mL). The mixture was stirred at80° C. for 12 hrs. On completion, the mixture was concentrated in vacuoto give the title compound (840 mg, 79% yield) as brown oil. LC-MS(ESI⁺) m/z 484.1 (M+Na)⁺.

Step 3—Tert-butyl2-[[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]methoxymethyl]morpholine-4-carboxylate

To a mixture of tert-butyl2-[[4-(3-carbamoyl-4-nitro-pyrazol-1-yl)phenyl]Methoxymethyl]morpholine-4-carboxylate (300 mg, 650 umol) in MeOH (3 mL) was addedPd/C (150 mg, 1.30 mmol) under H₂ (15 Psi), and the mixture was stirredat rt for 0.2 hr. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound (275 mg, 98% yield) asbrown oil. LC-MS (ESI⁺) m/z 454.1 (M+Na)⁺.

[4-[(1-Tert-butoxycarbonyl-2-piperidyl)ethoxymethyl]phenyl]boronic acid(Intermediate ML)

Step 1—Tert-Butyl2-[(4-bromophenyl)methoxymethyl]morpholine-4-carboxylate

To a mixture of 1-bromo-4-(bromomethyl)benzene (1.15 g, 4.60 mmol, CAS#3433-80-5), tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.50g, 2.30 mmol, CAS #157634-00-9) and TBAI (85.0 mg, 0.23 mmol) in DMF (10mL) was added NaH (184 mg, 4.60 mmol, 60% oil dispersion) at 0° C. Themixture was stirred at rt for 12 hrs. On completion, the reactionmixture was concentrated in vacuo. The mixture was poured into asolution of saturated sodium bicarbonate (20 mL) and extracted withethyl acetate (2×20 mL). The combined organic phase was washed withbrine (2×30 mL), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuo at 45° C. The residue was purified by silica gel chromatographyto give the title compound (554 mg, 62% yield) as brown oil. ¹H NMR (400MHz, CDCl₃) δ 7.39 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 4.43 (s,2H), 3.96-3.63 (m, 3H), 3.41 (dd, J=4.8, 8.0 Hz, 4H), 2.94-2.59 (m, 2H),1.39 (s, 9H).

Step2—Tert-butyl2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxymethyl]piperidine-1-carboxylate

To a mixture of tert-butyl2-[(4-bromophenyl)methoxymethyl]piperidine-1-carboxylate (5.00 g, 13.0mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(3.30 g, 13.0 mmol) in dioxane (50 mL) was added dioxane (50 mL) andKOAc (2.55 g, 26.0 mmol) and Pd(dppf)Cl₂·CH₂Cl₂ (1.06 g, 1.30 mmol). Thereaction mixture was stirred at 100° C. for 12 hrs. On completion, themixture was concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (3.20 g, 57% yield) as brownoil. ¹H NMR (400 MHz, CDCl₃) δ 7.88-7.77 (m, 2H), 7.41-7.33 (m, 2H),4.65-4.53 (m, 3H), 3.99 (d, J=10.8 Hz, 1H), 3.61-3.52 (m, 1H), 3.63-3.47(m, 1), 2.85-2.65 (m, 1), 1.90-1.72 (m, 1H), 1.88-1.71 (m, 1H),1.66-1.53 (m, 3H), 1.47 (s, 9H), 1.37 (s, 12H).

Step3—[4-[(1-Tert-butoxycarbonyl-2-piperidyl)ethoxymethyl]phenyl]boronicacid

To a mixture of tert-butyl2-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methoxymethyl]piperidine-1-carboxylate (3.20 g, 7.42 mmol) in THF (60 mL) and H₂O (12mL) was added NaIO₄ (4.76 g, 22.2 mmol, 1.2 mL). Then HCl (3 M, 4.95 mL)was added to the mixture. The reaction mixture was stirred at rt for 12hrs. On completion, the mixture was diluted with H₂O (30 mL), andextracted with EA (3×30 mL). The organic layers were washed with brine(3×20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by column chromatography to give thetitle compound (1.50 g, 58% yield) as brown oil. ¹H NMR (400 MHz,DMSO-d₆) δ 8.02 (s, 2H), 7.76 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H),4.58-4.44 (m, 2H), 4.30 (s, 1H), 3.82 (d, J=12.4 Hz, 1H), 3.58-3.47 (m,2H), 3.35 (s, 3H), 2.79-2.63 (m, 1H), 1.70 (d, J=7.2 Hz, 1H), 1.59-1.41(m, 4H), 1.37 (s, 9H), 1.32-1.21 (m, 1H).

Tert-Butyl2-[[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]methoxymethyl]piperidine-1-carboxylate(Intermediate MM)

Step 1—Tert-Butyl2-[[4-(3-methoxycarbonyl-4-nitro-pyrazol-1-yl)phenyl]methoxymethyl]piperidine-1-carboxylate

To a mixture of[4-[(1-tert-butoxycarbonyl-2-piperidyl)methoxymethyl]phenyl]boronic acid(1.50 g, 4.30 mmol, Intermediate ML), and methyl4-nitro-1H-pyrazole-3-carboxylate (0.70 g, 4.08 mmol, CAS #170487-38-4)in DCM (20 mL) was added pyridine (1.36 g, 17.2 mmol) and Cu(OAc)₂ (1.17g, 6.44 mmol) under oxygen. The reaction mixture was stirred at rt for12 hrs. On completion, the mixture was concentrated in vacuo. Theresidue was purified by column chromatography to give the title compound(1.50 g, 73% yield)) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75(s, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.55-7.50 (m, 2H), 4.64-4.51 (m, 2H),4.41-4.29 (m, 2H), 3.95 (s, 3H), 3.63-3.50 (m, 2H), 3.45 (d, J=7.6 Hz,1H), 1.61-1.42 (m, 6H), 1.38 (s, 9H).

Step 2—Tert-Butyl2-[[4-(3-carbamoyl-4-nitro-pyrazol-1-yl)phenyl]methoxymethyl]piperidine-1-carboxylate

To a sealed tube was added a mixture of tert-butyl2-[[4-(3-methoxycarbonyl-4-nitro-pyrazol-1-yl)phenyl]methoxymethyl]piperidine-1-carboxylate (1.50 g, 3.16 mmol) inMeOH (10 mL). Then NH₃·H₂O (1.33 g, 9.48 mmol, 1.46 mL) was added andthe mixture was stirred at 80° C. for 12 hrs. On completion, the mixturewas concentrated in vacuo to give the title compound (850 mg, 58% yield)as brown oil. LC-MS (ESI⁺) m/z 482.2 (M+Na)⁺.

Step 3—Tert-Butyl2-[[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]methoxymethyl]piperidine-1-carboxylate

To a mixture of tert-butyl2-[[4-(3-carbamoyl-4-nitro-pyrazol-1-yl)phenyl]methoxymethyl]piperidine-1-carboxylate(300 mg, 653 umol) in MeOH (3 mL) was added Pd/C (120 mg, 652.89 umol)under H₂ (15 Psi). The mixture was stirred at rt for 0.3 hour. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (265 mg, 94% yield) as brown oil. LC-MS(ESI⁺) m/z 452.1 (M+Na)⁺.

4-[3-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]prop-1-ynyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate MN)

To a mixture of tert-butylN-[2-[2-[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(300 mg, 510 umol, synthesized via Step 1 of Intermediate HA) in DCM (3mL) was added HCl/dioxane (4 M, 0.3 mL). The reaction mixture wasstirred at rt for 0.5 hr. On completion, the mixture was concentrated invacuo to give the title compound (245 mg, 91% yield) as a brown solid.LC-MS (ESI⁺) m/z 488.3 (M+H)⁺.

2-(2-Methyl-4-pyridyl)oxazole-4-carboxylic Acid (Intermediate MO)

Step 1—Ethyl 2-(2-methylpyridin-4-yl)oxazole-4-carboxylate

To a solution of 4-bromo-2-methyl-pyridine (1.50 g, 8.72 mmol, from CAS#22282-99-1) and ethyl oxazole-4-carboxylate (1.23 g, 8.72 mmol, fromCAS #170487-38-4) in DMF (40 mL) was added tris-o-tolylphosphane (531mg, 1.74 mmol), Pd(OAc)₂ (196 mg, 872 umol) and Cs₂CO₃ (5.68 g, 17.4mmol). The reaction mixture was stirred at 70° C. for 12 hours undernitrogen. On completion, the reaction mixture was filtered andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (1.10 g, 44% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J=5.2 Hz, 1H),8.31-8.36 (m, 1H), 7.86 (s, 1H), 7.75 (d, J=5.2 Hz, 1H), 4.44 (q, J=7.2Hz, 2H), 2.64 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); LC-MS (ESI⁺) m/z 233.1(M+H)⁺.

Step 2—2-(2-Methyl-4-pyridyl)oxazole-4-carboxylic Acid

To a solution of ethyl 2-(2-methyl-4-pyridyl)oxazole-4-carboxylate (1.10g, 4.74 mmol) in THF (20 mL) was added LiOH H₂O (795 mg, 19.0 mmol) inH₂O (4 mL). The reaction mixture was stirred at rt for 12 hours. Oncompletion, the reaction mixture was filtered and the filter cake wasdissolved in water (20 mL). The solution was acidified to pH=4 andfiltered. The filter cake was washed with water (2×5 mL) and dried invacuo. The residue was purified by prep-HPLC to give the title compound(600 mg, 52% yield) as a white solid.

4-[3-Carbamoyl-4-[[2-(2-methyl-4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid (Intermediate MP)

Step1—Methyl4-[3-carbamoyl-4-[[2-(2-methyl-4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate

To a solution of 2-(2-methyl-4-pyridyl)oxazole-4-carboxylic acid (200mg, 831.11 umol, HCl, Intermediate MO) and methyl4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate (173 mg, 665 umol,Intermediate CL) in DMF (20 mL) was added DIPEA (322 mg, 2.49 mmol) andHATU (379 mg, 997 umol). The reaction mixture was stirred at rt for 0.5hour. On completion, the reaction mixture was quenched with water (5 mL)and filtered. The filter cake was washed with water (3×3 mL) and driedin vacuo to give the title compound (200 mg, 53% yield) as a whitesolid. LC-MS (ESI⁺) m/z 447.3 (M+H)⁺.

Step2—4-[3-Carbamoyl-4-[[2-(2-methyl-4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid

To a solution of methyl4-[3-carbamoyl-4-[[2-(2-methyl-4-pyridyl)oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoate(150 mg, 336 umol) in THF (20 mL) and MeOH (4 mL) was added LiOH·H₂O(42.3 mg, 1.01 mmol) in H₂O (4 mL). The reaction mixture was stirred atrt for 12 hours. On completion, the reaction mixture was poured into HCl(1N, 2 mL) and concentrated in vacuo to give the title compound (200 mg,100% yield) as a white solid. LC-MS (ESI⁺) m/z 433.2 (M+H)⁺.

2-(2-Cyclopropyl-4-pyridyl)oxazole-4-carboxylic Acid (Intermediate MO)

Step 1—Ethyl 2-(2-cyclopropyl-4-pyridyl)oxazole-4-carboxylate

To a solution of 4-bromo-2-cyclopropyl-pyridine (512 mg, 2.59 mmol, CAS#1086381-28-3) and ethyl oxazole-4-carboxylate (365 mg, 2.59 mmol, CAS#170487-38-4) in DMF (5 mL) was added tris-o-tolylphosphane (157 mg, 517umol), Pd(OAc)₂ (58.0 mg, 259 umol) and Cs₂CO₃ (1.68 g, 5.17 mmol). Thereaction mixture was stirred at 70° C. for 12 hours under nitrogen. Oncompletion, the reaction mixture was diluted with EA (100 mL), pouredinto sat.NH₄Cl (50 mL) and extracted with EA (3×50 mL). The combinedorganic layers were washed with brine (50 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica column chromatography (PE/EA, 10/1 to 5/1) to give the titlecompound (380 mg, 55% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.57 (d, J=4.8 Hz, 1H), 8.33 (s, 1H), 7.82 (s, 1H), 7.67 (dd, J=1.6,5.2 Hz, 1H), 4.44 (q, J=7.2 Hz, 2H), 2.16-2.07 (m, 1H), 1.42 (t, J=7.2Hz, 3H), 1.12-1.02 (m, 4H). LC-MS (ESI⁺) m/z 259.1 (M+H)⁺.

Step 2—2-(2-Cyclopropyl-4-pyridyl)oxazole-4-carboxylic Acid

To a solution of ethyl 2-(2-cyclopropyl-4-pyridyl)oxazole-4-carboxylate(370 mg, 1.43 mmol) in THF (20 mL) was added a solution of LiOH H₂O (150mg, 3.57 mmol) in H₂O (4 mL). The reaction mixture was stirred at rt for12 hours. On completion, the reaction mixture was quenched with 4 mL ofHCl (1N) and concentrated in vacuo to give the title compound (450 mg,100% yield) as a white solid. LC-MS (ESI⁺) m/z 231.1 (M+H)⁺.

2-(2-(2-Aminoethoxy)ethoxy)ethanol (Intermediate MR)

To a solution of tert-butylN-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (1.60 g, 6.42 mmol, fromCAS #139115-92-7) in DCM (10 mL) was added HCl/dioxane (4 M, 1.60 mL).The reaction mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(1.19 g, 100% yield) as colorless oil.

4-[2-[2-(2-Azidoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate MS)

Step1—2-(2,6-Dioxopiperidin-3-yl)-4-((2-(2-(2-hydroxyethoxy)ethoxy)ethyl)amino)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (1.50 g, 5.43mmol, Intermediate R) and 2-[2-(2-aminoethoxy)ethoxy]ethanol (1.01 g,5.43 mmol, HCl, Intermediate MR) in DMF (5 mL) was added DIPEA (2.81 g,21.7 mmol). The reaction mixture was stirred at 115° C. for 12 hours. Oncompletion, the reaction mixture was poured into sat.NaHCO₃ (30 mL) andextracted with EA (3×100 mL). The combined organic layers were washedwith brine (100 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography (PE/EA, 1/1 to 0/1) to give the title compound (600 mg,27% yield) as a yellow solid. LC-MS (ESI⁺) m/z 406.2 (M+H)⁺.

Step2—2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethylMethanesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-(2-hydroxyethoxy)ethoxy]ethylamino]isoindoline-1,3-dione(100 mg, 247 umol) in DCM (5 mL) was added TEA (49.9 mg, 493 umol) andMsCl (37.0 mg, 323 umol) at 0° C. The reaction mixture was then stirredat rt for 0.5 hour. On completion, the reaction mixture was concentratedin vacuo to give title compound (130 mg, 100% yield) as a yellow solid.LC-MS (ESI⁺) m/z 484.2 (M+H)⁺.

Step3—4-[2-[2-(2-Azidoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl methanesulfonate (60.0 mg, 124 umol) in DMF (3 mL) was added NaN₃(16.1 mg, 248 umol). The reaction mixture was stirred at 65° C. for 2hours. On completion, the reaction mixture was poured into sat. NaHCO₃(30 mL) and extracted with DCM (2×50 mL). The combined organic layerswere washed with brine (50 mL), dried with anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (60.0 mg, 100%yield) as a yellow solid. LC-MS (ESI⁺) m/z 453.2 (M+Na)⁺.

4-Amino-1-prop-2-ynyl-pyrazole-3-carboxamide (Intermediate MT)

Step 1—4-Nitro-1-(prop-2-yn-1-yl)-1H-pyrazole-3-carboxamide

To a solution of 4-nitro-1H-pyrazole-3-carboxamide (2.00 g, 12.8 mmol,Intermediate CJ) and 3-bromoprop-1-yne (3.05 g, 25.6 mmol, 2.21 mL) inDMF (30 mL) was added K₂CO₃ (3.54 g, 25.6 mmol). The reaction mixturewas stirred at 60° C. for 1 hour. On completion, the reaction mixturewas diluted with EA (50 mL) and filtered, then the filtrate wasconcentrated in vacuo. The residue was purified by silica columnchromatography (PE/EA, 1/1 to 0/1) to give the title compound (1.30 g,52% yield) as an off-white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 8.90 (s,1H), 8.07 (s, 1H), 7.82 (s, 1H), 5.14 (d, J=2.4 Hz, 2H), 3.67 (t, J=2.4Hz, 1H), 2.73 (s, 1H).

Step 2—4-Amino-1-prop-2-ynyl-pyrazole-3-carboxamide

To a solution of 4-nitro-1-prop-2-ynyl-pyrazole-3-carboxamide (1.20 g,6.18 mmol) in MeOH (30 mL) was added a solution of NH₄Cl (1.65 g, 30.9mmol) in H₂O (10 mL) and Fe (1.73 g, 30.9 mmol). The reaction mixturewas stirred at 80° C. for 12 hours under nitrogen. On completion, thereaction mixture was diluted with DCM (400 mL), stirred at rt for 10min, then washed with brine (2×50 mL). The organic layer was dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (800 mg, 79% yield) as a light yellow solid.

2-(2-Prop-2-ynoxyethoxy)ethanamine (Intermediate MU)

To a mixture of tert-butyl N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate(2.50 g, 10.3 mmol, synthesized via Step 1 of Intermediate CQ) in DCM(20 mL) was added HCl/dioxane (4 M, 5.14 mL) and the reaction wasstirred at rt for 0.5 hr. On completion, the mixture was concentrated invacuo to give the title compound (1.80 g, 97% yield, HCl) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 2H), 4.14 (d, J=2.4 Hz, 2H),3.62 (t, J=5.6 Hz, 2H), 3.59-3.54 (m, 4H), 3.45 (t, J=2.4 Hz, 1H),2.91(s, 2H).

2-(2,6-Dioxo-3-piperidyl)-4-[2-(2-prop-2-vnoxyethoxy)ethylamino]isoindoline-1,3-dione(Intermediate MV)

To a mixture of 2-(2-prop-2-ynoxyethoxy)ethanamine (1.80 g, 10.0 mmol,HCl, Intermediate MU) in dioxane (30 mL) was added DIPEA (3.88 g, 30.0mmol, 5.24 mL), and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (2.77 g, 10.0mmol, Intermediate R) into the mixture. The reaction mixture was stirredat 115° C. for 12 hrs. On completion, the mixture was concentrated invacuo. The residue was purified by column chromatography to give thetitle compound (1.10 g, 27% yield) as a brown solid. ¹H NMR (400 MHz,CDCl₃) δ 8.61 (s, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.10 (d, J=7.2 Hz, 1H),6.93 (d, J=8.8 Hz, 1), 6.49 (t, J=5.6 Hz, 1), 4.98-4.89 (m, 1), 4.21 (d,J=2.4 Hz, 2H), 3.75-3.70 (m, 6H), 3.49 (q, J=5.6 Hz, 2H), 2.90-2.73 (m,3H), 2.46 (t, J=2.4 Hz, 1H), 2.18-2.06 (m, 1H).

4-(Azetidin-3-ylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate MW)

Step 1—Tert-Butyl3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]azetidine-1-carboxylate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (500 mg,1.81mmol, Intermediate R) and tert-butyl 3-aminoazetidine-1-carboxylate(374 mg, 2.17 mmol, CAS #193269-78-2) in DMSO (20 mL) was added DIPEA(702 mg, 5.43 mmol). The reaction mixture was stirred at 90° C. for 15hrs. On completion, the reaction mixture was filtered and acidified topH=5. The crude product was purified by reversed phase (0.1% HClcondition) to give the title compound (350 mg, 44% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.61 (t, J=8.0 Hz,1H), 7.13 (d, J=7.2 Hz, 1H), 6.96 (d, J=8.4 Hz, 1), 6.89 (d, J=6.4 Hz,1H), 5.08 (dd, J=5.2, 12.8 Hz, 1H), 4.49-4.41 (m, 1H), 4.19-4.23 (m,2H), 3.80-3.84 (m, 2H), 2.95-2.84 (m, 1H), 2.95-2.84 (m, 1H), 2.65-2.60(m, 1H), 2.54-2.52 (m, 1), 2.09-1.99 (m, 1), 1.39 (s, 9H).

Step2—4-(Azetidin-3-ylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butyl3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]azetidine-1-carboxylate(430 mg, 1.00 mmol) in DCM (5 mL) was added HCl/dioxane (4 M, 5.12 mL).The reaction mixture was stirred at rt for 1 hr. On completion, thereaction mixture was concentrated in vacuo to give the title compound(430 mg, 100% yield, HCl) as a yellow solid. LC-MS (ESI⁺) m/z 329.0(M+H)⁺.

4-[[1-[2-[2-(2-aminoethoxy)ethoxy]ethyl]azetidin-3-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate MX)

Step 1—Tert-ButylN-[2-[2-[2-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]azetidin-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of4-(azetidin-3-ylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(250 mg, 685 umol, Intermediate MW) and tert-butylN-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (220 mg, 891 umol,Intermediate HY) in DCM (10 mL) and THF (20 mL) was added KOAc (135 mg,1.37 mmol) and NaBH(OAc)₃ (218 mg, 1.03 mmol). The reaction mixture wasstirred at rt for 2 hrs. On completion, the reaction mixture wasquenched with water (2 mL), and concentrated in vacuo. The crude productwas purified by reversed phase (acidified condition: 0.10% FA) to givethe title compound (270 mg, 66% yield) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 7.72-7.54 (m, 1H), 7.09 (d, J=8.8 Hz, 1), 7.01(d, J=8.8 Hz, 1), 6.76-6.74 (m, 1H), 6.61 (d, J=6.8 Hz, 1H), 5.07 (dd,J=5.2, 12.8 Hz, 1H), 4.34-4.19 (m, 1H), 3.70 (t, J=6.8 Hz, 2H),3.50-3.36 (m, 10H), 3.06 (q, J=6.0 Hz, 2H), 3.00-2.96 (m, 2H), 2.92-2.84(m, 1H), 2.65-2.61 (m, 2H), 2.09-2.01 (m, 1H), 1.37 (s, 9H); LC-MS(ESI⁺) m/z 560.1 (M+H)⁺.

Step2—4-[[1-[2-[2-(2-aminoethoxy)ethoxy]ethyl]azetidin-3-yl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]azetidin-1-yl]ethoxy]ethoxy]ethyl]carbamate (270 mg, 483 umol) in DCM (5mL) was added HCl/dioxane (4 M, 121 uL). The reaction mixture wasstirred at 20° C. for 1 hr. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (239 mg, 100% yield,HCl salt) as a yellow solid. LC-MS (ESI⁺) m/z 460.3 (M+H)⁺.

5-[2-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate MY)

Step1—5-(But-3-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of 2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione(650 mg, 2.35 mmol, Intermediate HX), but-3-yn-1-amine (373 mg, HCl, CAS#14044-63-4) in DMSO (10 mL) was added DIPEA (3.04 g, 23.5 mmol) andstirred at 130° C. for 1 hr. On completion, the mixture was poured intowater (20 mL). The aqueous phase was extracted with ethyl acetate (2×20mL). The combined organic phase was washed with brine (2×30 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate-1:1) to give the title compound (386 mg, 50% yield) as a brownsolid; LC-MS (ESI⁺) m/z 326.0 (M+H)⁺.

Step2—Tert-butylN-[2-[2-[2-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a mixture of5-(but-3-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (200mg, 0.615 mmol), tert-butylN-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (506 mg, 1.84 mmol,Intermediate ID) in THF (5 mL) was added chlororuthenium(1+);1,2,3,4,5-pentamethylcyclopenta-1,3-diene; triphenylphosphane (24.4 mg,0.030 mmol). The mixture was stirred at 65° C. for 12 hrs. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate-1:1) to give the title compound (210 mg, 54% yield) as a brownoil; LC-MS (ESI⁺) m/z 600.2 (M+H)⁺.

Step3—5-[2-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butyl N-[2-[2-[2-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (210 mg, 350umol) in DCM (5 mL) was added HCl/dioxane (4 M, 87.5 uL) and stirred at15° C. for 0.5 hr. On completion, the mixture was concentrated in vacuoto give the title compound (185 mg, 98% yield, HCl) brown oil. LC-MS(ESI⁺) m/z 500.2 (M+H)⁺.

2-(2,6-Dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (IntermediateMZ)

To a solution of 5-hydroxyisobenzofuran-1,3-dione (1.00 g, 6.09 mmol,CAS #27550-59-0) and 3-aminopiperidine-2,6-dione (1.05 g, 6.40 mmol,HCl) in HOAc (20 mL) was added KOAc (1.79 g, 18.3 mmol). The mixture wasstirred at 90° C. for 6 hrs. On completion, the mixture was poured intoice water (100 mL), and solid was obtained and then filtered. Theresidue was washed with H₂O (3×50 mL), dried in vacuo to give the titlecompound (1.40 g, 83% yield) as a light white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.29-10.90 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.39-6.87 (m,2H), 5.09 (dd, J=5.4, 12.8 Hz, 1), 3.34 (s, 1), 2.96-2.82 (m, 1H),2.69-2.58 (m, 1), 2.08-1.99 (m, 1H).

2-(2,6-Dioxo-3-piperidyl)-5-prop-2-ynoxy-isoindoline-1,3-dione(Intermediate NA)

To a solution of2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (1.40 g, 5.11mmol, Intermediate MZ) in DMF (20 mL) was added K₂CO₃ (847 mg, 6.13mmol) and 3-bromoprop-1-yne (668 mg, 5.62 mmol, 484 uL). The mixture wasstirred at 15° C. for 6 hrs. On completion, the residue was diluted withH₂O (50 mL) and extracted with EA (3×50 mL). The combined organic layerswere washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated to give a residue. The residue was purified by reversedphase (FA condition) to give the title compound (0.700 g, 43% yield) asa light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.89(d, J=8.4 Hz, 1H), 7.53 (d, J=2.4 Hz, 1H), 7.41 (dd, J=2.4, 8.4 Hz, 1),5.14 (dd, J=5.4, 12.8 Hz, 1), 5.07 (d, J=2.0 Hz, 2H), 3.70 (t, J=2.4 Hz,1H), 3.41-3.35 (m, 1H), 2.97-2.83 (m, 1H), 2.65-2.52 (m, 2H), 2.11-2.01(m, 1H); LC-MS (ESI⁺) m/z 313.2 (M+H)⁺.

5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate NB)

Step 1—Tert-ButylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-prop-2-ynoxy-isoindoline-1,3-dione (0.6 g,1.92 mmol, Intermediate NA), CuSO₄ (3.07 mg, 19.2 umol) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (7.61mg, 38.4 umol) in H₂O (3 mL) and t-BuOH (3 mL) was added tert-butylN-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (527.06 mg, 1.92 mmol,Intermediate ID). The mixture was stirred at 60° C. for 2 hrs. Oncompletion, the mixture was diluted with H₂O (20 ml), extracted with EA(2×30 ml), washed with brine (50 ml), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by reversed phase (FAcondition) to give the title compound (0.800 g, 71% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.25 (s, 1H), 7.85 (d,J=8.2 Hz, 1H), 7.61 (s, 1), 7.45 (d, J=8.2 Hz, 1H), 6.72 (s, 2H), 5.38(s, 2H), 5.17-5.09 (m, 1), 4.55 (s, 2H), 4.10-3.97 (m, 4H), 3.83 (s,2H), 3.65-3.51 (m, 13H), 3.07 (d, J=6.0 Hz, 4H), 2.88 (d, J=13.6 Hz,1H), 2.70-2.57 (m, 4H), 1.38 (s, 9H).

Step2—5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]triazol-4-yl]methoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxymethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (0.800 g, 1.36mmol) in DCM (10 mL) was added HCl/dioxane (4 M, 1 mL). The mixture wasstirred at rt for 30 minutes. On completion, the mixture wasconcentrated, to give the title compound (500 mg 70% yield, HCl) as ayellow solid. LC-MS (ESI⁺) m/z 487.3 (M+H)⁺.

5-But-3-ynoxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NC)

To a mixture of2-(2,6-dioxo-3-piperidyl)-5-hydroxy-isoindoline-1,3-dione (1.00 g, 3.65mmol, Intermediate MZ) and but-3-yn-1-ol (307 mg, 4.38 mmol, CAS#927-74-2) in THF (10 mL) was added PPh₃ (1.43 g, 5.47 mmol). Then DIAD(1.47 g, 7.29 mmol) was added into the mixture at 0° C. and the mixturewas stirred at rt for 12 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by column chromatography(SiO₂) to give the title compound (568 mg, 48% yield) as a brown solid.LC-MS (ESI⁺) m/z 327.0 (M+H)⁺.

5-[2-[3-[2-[2-(2-aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (Intermediate ND)

Step1—Tert-butylN-[2-[2-[2-[5-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]oxyethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a mixture of5-but-3-ynoxy-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (115 mg,352 umol, Intermediate NC), tert-butylN-[2-[2-(2-azidoethoxy)ethoxy]ethyl]carbamate (290 mg, 1.06 mmol,Intermediate ID) in THF (3 mL) was added chlororuthenium(1+);1,2,3,4,5-pentamethylcyclopenta-1,3-diene; triphenylphosphane (14.0 mg,17.6 umol). The mixture was stirred at 65° C. for 12 hrs. On completion,the mixture was concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂) to give the title compound (156 mg, 73%yield) as brown oil. LC-MS (ESI⁺) m/z 601.1 (M+H)⁺.

Step2—5-[2-[3-[2-[2-(2-aminoethoxy)ethoxy]ethyl]triazol-4-yl]ethoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[2-[2-[2-[5-[2-[2-(2,6-dioxo-3-piperidyl)-1, 3-dioxo-isoindolin-5-yl]oxyethyl]triazol-1-yl]ethoxy]ethoxy]ethyl]carbamate (156 mg, 259 umol)in DCM (2 mL) was added HCl/dioxane (4 M, 129 uL). The reaction mixturewas stirred at rt for 0.5 hr. On completion, the mixture wasconcentrated in vacuo. The residue was purified by reverse phase (0.10%FA condition) to give the title compound (135 mg, 96% yield, HCl) asbrown oil. LC-MS (ESI⁺) m/z 501.1 (M+H)⁺.

5-[2-[2-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NE)

Step 1—Tert-ButylN-[2-[2-[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (250 mg, 905umol, Intermediate HX) and tert-butylN-[2-[2-[4-[2-(2-aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate(343 mg, 950 umol, Intermediate IM) in DMSO (8 mL) was added DIPEA (351mg, 2.72 mmol). The reaction mixture was stirred at 130° C. for 13hours. On completion, the reaction mixture was quenched with water (2mL), concentrated in vacuo. The crude product was purified by reversedphase (acidified condition: 0.1% FA) to give the title compound (324 mg,55% yield) as a yellow oil. LC-MS (ESI⁺) m/z 517.2 (M+H−100)⁺.

Step2—5-[2-[2-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3—piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethyl]piperazin-1-yl]ethoxy]ethyl]carbamate (350 mg, 534umol) in DCM (5 mL) was added HC/dioxane (4 M, 133 uL). The reactionmixture was stirred at rt for 1 hr. On completion, the reaction mixturewas concentrated in vacuo to give the title compound (290 mg, 98% yield)as a yellow solid. LC-MS (ESI⁺) m/z 517.2 (M+H)⁺.

2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethylmethanesulfonate (Intermediate NF)

Step1—2-(2,6-Dioxopiperidin-3-yl)-5-((2-(2-hydroxyethoxy)ethyl)amino)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-5-fluoro-isoindoline-1,3-dione (500 mg, 1.81mmol, Intermediate HX) and 2-(2-aminoethoxy)ethanol (210 mg, 2.00 mmol)in DMSO (10.0 mL) was added DIPEA (702 mg, 5.43 mmol). The reactionmixture was stirred at 130° C. for 15 hrs. On completion, the mixturewas added H₂O (10.0 mL) and extracted with DCM (3×100 mL). The combinedorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated to give the title compound (250 mg, 38% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.62 (d,J=8.4 Hz, 1H), 7.01 (d, J=2.0 Hz, 1), 6.79 (dd, J=2.0, 8.4 Hz, 1), 5.05(s, 1), 4.95 (dd, J=5.2, 12.8 Hz, 1H), 3.81 (d, J=4.2 Hz, 2H), 3.78 (t,J=5.2 Hz, 2H), 3.68-3.63 (m, 2H), 3.45 (t, J=5.2 Hz, 2H), 2.95-2.70 (m,3H), 2.19-2.11 (m, 1H). LC-MS (ESI⁺) m/z 362.1 (M+H)⁺.

Step2—2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethylMethanesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-[2-(2-hydroxyethoxy)ethylamino]isoindoline-1,3-dione(300 mg, 830 umol) in DCM (20.0 mL) was added TEA (168 mg, 1.66 mmol)and MsCl (105 mg, 913 umol). The reaction mixture was stirred at rt for2 hrs. On completion, the reaction mixture was diluted with water (50mL) and extracted with DCM (2×100 mL). The organic layer was washed withbrine (20 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound (360 mg, 98% yield) asa yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (s, 1H), 7.64 (d, J=8.4Hz, 1), 7.02 (d, J=2.0 Hz, 1H), 6.83 (dd, J=2.0, 8.4 Hz, 1H), 5.03-4.89(m, 1H), 4.52-4.39 (m, 2H), 3.85-3.76 (m, 4H), 3.44 (t, J=5.2 Hz, 2H),3.10 (s, 3H), 2.96-2.72 (m, 3H), 2.24-2.10 (m, 1H).

5-[2-[2-[6-[2-(2-Aminoethoxy)ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NG)

Step 1—Tert-Butyl6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.31]heptane-2-carboxylate

To a solution of2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethylmethanesulfonate (260 mg, 592 umol, Intermediate NF) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (139 mg, 592 umol, HCl, CAS#1041026-70-3) in ACN (15.0 mL) was added NaHCO₃ (149 mg, 1.77 mmol) andTBAI (21.9 mg, 59.2 umol). The reaction mixture was stirred at 80° C.for 16 hrs. On completion, the mixture was concentrated in vacuo. Thecrude product was purified by silica gel chromatography (DCM:MeOH=20:1)to give the title compound (159 mg, 45% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.16 (s,1H), 7.01 (s, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.04 (dd, J=5.2, 12.8 Hz,1H), 3.86 (s, 4H), 3.54 (t, J=5.2 Hz, 2H), 3.44-3.35 (m, 10H), 2.96-2.80(m, 1H), 2.63-2.59 (m, 2H), 2.00 (d, J=10.8 Hz, 1H), 1.36 (s, 9H). LC-MS(ESI⁺) m/z 542.3 (M+H)⁺.

Step2—5-[2-[2-(2,6-Diazaspiro[3.3]heptan-2-yl)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butyl6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate (177 mg, 327umol) in DCM (5.00 mL) was added TFA (2.48 g, 21.7 mmol). The reactionmixture was stirred at rt for 1 hr. On completion, the mixture wasconcentrated in vacuo. Then, the residue was diluted with anhydroustoluene (30.0 mL). Then the mixture was concentrated in vacuo to givethe title compound (181 mg, 100% yield, TFA) as a yellow solid. LC-MS(ESI⁺) m/z 442.3 (M+H)⁺.

Step 3—Tert-ButylN-[2-[2-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]ethyl]carbamate

To a solution of5-[2-[2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (181 mg, 327 umol, TFA) and tert-butylN-[2-(2-oxoethoxy)ethyl]carbamate (230 mg, 1.13 mmol, synthesized viaStep 1 of Intermediate FS) in a mixed solvent of THF (15.0 mL) and DMF(5.00 mL) was added TEA (66.1 mg, 654 umol) and HOAc (78.5 mg, 1.31mmol). The reaction mixture was stirred at rt for 12 hrs. After,NaBH(OAc)₃ (83.1 mg, 392 umol) was added and the resulting reactionmixture was stirred at rt for 24 hrs. On completion, the mixture wasquenched with water (1.00 mL). The mixture was concentrated in vacuo.The crude product was purified by reversed phase (condition: 0.10% FA)to give the title compound (77 mg, 34% yield) as yellow solid. LC-MS(ESI⁺) m/z 629.4 (M+H)⁺.

Step4—5-[2-[2-[6-[2-(2-Aminoethoxy)ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptan-2-yl]ethoxy]ethyl]carbamate(100 mg, 151 umol) in DCM (5.00 mL) was added TFA (86.2 mg, 756 umol).The reaction mixture was stirred at rt for 1 hr. On completion, thereaction mixture was concentrated in vacuo to give the title compound(97 mg, 100% yield, TFA) as a yellow solid. LC-MS (ESI⁺) m/z 529.4(M+H)⁺.

4-(Aminomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NH)

Step 1—Tert-ButylN-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]methyl]carbamate

To a solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(700 mg, 2.08 mmol, Intermediate FT) and potassium N-Boc-aminomethyltrifluoroborate (738 mg, 3.11 mmol, CAS #1314538-55-0) in dioxane(10 mL) and H₂O (2 mL) was added K₂CO₃ (861 mg, 6.23 mmol) andPd(dppf)Cl₂·CH₂Cl₂ (170 mg, 208 umol). The reaction mixture was stirredat 85° C. for 6 hours under nitrogen. On completion, the reactionmixture was poured into brine (30 mL) and extracted with EA (3×80 mL).The combined organic layers were washed with brine (80 mL), dried withanhydrous Na₂SO₄, filtered, concentrated in vacuo. The residue waspurified by silica column chromatography (PE/EA, 3/1 to 1/1) to give thetitle compound (270 mg, 34% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.11 (s, 1H), 7.88-7.77 (m, 2H), 7.74-7.64 (m, 1H),5.20-5.09 (m, 1H), 4.69-4.54 (m, 2H), 3.02-2.79 (m, 1H), 2.69-2.56 (m,2H), 2.17-2.01 (m, 1H), 1.41 (s, 9H).

Step 2—4-(Aminomethyl)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]methyl]carbamate(80.0 mg, 207 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 12.3 mL).The reaction mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(60.0 mg, 90% yield) as yellow oil.

5-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]methanesulfonate(Intermediate NI)

Step1—2-(2,6-Dioxo-3-piperidyl)-4-(5-hydroxypent-1-Ynyl)isoindoline-1,3-dione

To a solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1.00 g, 2.97 mmol, Intermediate FT) and pent-4-yn-1-ol (499 mg, 5.93mmol, CAS #5390-04-5) in DMF (10 mL) was added Pd(PPh₃)₂Cl₂ (208 mg, 296umol), TEA (5.40 g, 53.3 mmol, 7.43 mL), and CuI (56.4 mg, 296 umol)under N₂. The reaction mixture was stirred at 80° C. for 30 min undermicrowave. On completion, the reaction mixture was diluted with EA (20mL), filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=5:1 to 1:1)to give the title compound (800 mg, 76% yield) as a light yellow solid.LC-MS (ESI⁺) m/z 341.1 (M+H)⁺.

Step2—2-(2,6-Dioxo-3-piperidyl)-4-(5-hydroxypentyl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-(5-hydroxypent-1-ynyl)isoindoline-1,3-dione(800 mg, 2.35 mmol) in THF (25 mL) was added Pd/C (100 mg, 2.35 mmol, 10wt %) and Pd(OH)₂/C (100 mg, 71.2 umol, 10 wt %). The reaction mixturewas stirred at rt for 12 hours under H₂ (15 psi). On completion, theresidue was filtered and the filtrate was concentrated in vacuo to givethe title compound (810 mg, 95% yield) as a black brown solid. LC-MS(ESI⁺) m/z 345.3 (M+H)⁺.

Step 3—5-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]pentylMethanesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-(5-hydroxypentyl)isoindoline-1,3-dione (300mg, 871 umol) and TEA (264 mg, 2.61 mmol, 363 uL) in DCM (5 mL) wasadded MsCl (119 mg, 1.05 mmol, 80.9 uL). The reaction mixture wasstirred at rt for 0.5 hour. The mixture was quenched by addition of H₂O(50 mL), then extracted with DCM (2×100 mL). The organic phase wasconcentrated in vacuo to give the title compound (370 mg, 90% yield) asa yellow solid. LC-MS (ESI⁺) m/z 423.2 (M+H)⁺.

2-[2-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]ethoxy]ethylMethanesulfonate (Intermediate NJ)

Step1—2-(2,6-Dioxo-3-piperidyl)-4-[(Z)-2-(2-hydroxyethoxy)vinyl]isoindoline-1,3-dione

To a solution of 4-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1.5 g, 4.45 mmol, Intermediate FT) and 2-vinyloxyethanol (784 mg, 8.90mmol, CAS #764-48-7) in dioxane (100 mL) was added P(t-Bu)₃ (1.80 g, 889umol, 2.09 mL, 10% purity), DIPEA (690 mg, 5.34 mmol, 930 uL) andPd₂(dba)₃ (407 mg, 444 umol). The reaction mixture was stirred at rt for12 hours under N₂. On completion, the reaction mixture was poured intosat.NH₄Cl (30 mL) and extracted with EA (3×100 mL). The combined organiclayers were washed with brine (50 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=2:1 to 0:1) to givethe title compound (600 mg, 33% yield) as a light yellow solid. LC-MS(ESI⁺) m/z 345.1 (M+H)⁺.

Step2—2-(2,6-Dioxo-3-piperidyl)-4-[2-(2-hydroxyethoxy)ethyl]isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[(Z)-2-(2-hydroxyethoxy)vinyl]isoindoline-1,3-dione(500 mg, 1.45 mmol) in THF (20 mL) was added Pd/C (50 mg, 1.45 mmol, 10wt %). The reaction mixture was stirred at rt for 24 hours under H₂ (15Psi). Then Pd(OH)₂/C (50 mg, 35.6 umol, 10 wt %) was added. The reactionmixture was stirred at rt for 12 hours under H₂ (15 Psi). On completion,the residue was filtered and the filtrate was concentrated in vacuo togive the title compound (600 mg, 85% purity) as a light yellow solid.LC-MS (ESI⁺) m/z 347.2 (M+H)⁺.

Step3—2-[2-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]ethoxy]ethylMethanesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-(2-hydroxyethoxy)ethyl]isoindoline-1,3-dione(250 mg, 721.85 umol) in DCM (10 mL) was added TEA (219 mg, 2.17 mmol,301 uL) and MsCl (124 mg, 1.08 mmol, 83.8 uL) at 0° C. The reactionmixture was stirred at rt for 30 min. The mixture was quenched byaddition H₂O (50 mL), then extracted with DCM (2×100 mL). The organicphase was concentrated in vacuo to give the title compound (310 mg, 63%purity) as a yellow solid. LC-MS (ESI⁺) m/z 425.0 (M+H)⁺.

4-[2-[2-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NK)

Step1—4-[2-[2-[4-[3-(Difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of2-[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]ethoxy]ethylmethanesulfonate (300 mg, 706 umol, Intermediate NJ) and4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine (199 mg, 706 umol,HCl, Intermediate JP) in CH₃CN (20 mL) was added NaHCO₃ (178 mg, 2.12mmol) and KI (11.7 mg, 70.6 umol). The reaction mixture was stirred at80° C. for 12 hours. On completion, the mixture was filtered, and thefiltrate was concentrated in vacuo to give the title compound (410 mg,85% purity) as a yellow solid. LC-MS (ESI⁺) m/z 575.2 (M+H)⁺.

Step2—4-[2-[2-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of4-[2-[2-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]ethoxy]ethyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(260 mg, 452 umol) in THF (10 mL) was added PtO₂ (41.1 mg, 181 umol),the reaction mixture was stirred at rt under H₂ (15 psi) for 16 hrs. Oncompletion, the mixture was filtered, the filtrate was concentrated wasconcentrated in vacuo to give the title compound (40 mg, 16% yield) as awhite solid. LC-MS (ESI⁺) m/z 545.3 (M+H)⁺.

4-[5-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]pentyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NL)

Step1—4-[5-[4-[3-(Difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]pentyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of5-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]pentylmethanesulfonate (260 mg, 615 umol, Intermediate NI) and4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine (133 mg, 473 umol,HCl, Intermediate JP) in ACN (15 mL) was added NaHCO₃ (119 mg, 1.42mmol, 55.2 uL) and KI (7.86 mg, 47.3 umol), the reaction mixture wasstirred at 80° C. for 16 hr. On completion, the mixture was filtered,and the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography (SiO₂, DCM/MeOH-100/1 to 50/1) to give the titlecompound (140 mg, 51% yield) as a white solid. LC-MS (ESI⁺) m/z 573.3(M+H)⁺.

Step2—4-[5-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]pentyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of4-[5-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]pentyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(190 mg, 331 umol) in THF (5 mL) was added PtO₂ (37.6 mg, 165 umol), andthe reaction mixture was stirred at rt under H₂ (15 psi) for 3 hrs. Oncompletion, the mixture was filtered, the filtrate was concentrated invacuo to give the title compound (180 mg, 99% yield) as a white solid.LC-MS (ESI⁺) m/z 543.4 (M+H)⁺.

3-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propylMethanesulfonate (Intermediate NM)

Step1—2-(2,6-Dioxo-3-piperidyl)-4-(3-hydroxyprop-1-ynyl)isoindoline-1,3-dione

4-Bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (1.00 g, 2.97mmol, Intermediate FT), prop-2-yn-1-ol (332 mg, 5.93 mmol, CAS#107-19-7), Pd(PPh₃)₂Cl₂ (208 mg, 296 umol), CuI (113 mg, 593 umol), andTEA (5.40 g, 53.4 mmol) were taken up into a microwave tube in DMF (20mL). The sealed tube was heated at 80° C. for 0.5 hr under microwave. Oncompletion, the mixture was poured into water (100 mL). The aqueousphase was extracted with ethyl acetate (2×50 mL). The combined organicphase was washed with brine (2×40 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=0:1) to give thetitle compound (185 mg, 9% yield) as white solid. LC-MS (ESI⁺) m/z 335.0(M+Na)⁺.

Step2—2-(2,6-Dioxo-3-piperidyl)-4-(3-hydroxypropyl)isoindoline-1,3-dione

To a mixture of 2-(2,6-dioxo-3-piperidyl)-4-(3-hydroxyprop-1-ynyl)isoindoline-1,3-dione (320mg, 1.02 mmol) in THF (10 mL) was added Pd/C (2.05 mmol, 10 wt %), andPd(OH)₂ (288 mg, 2.05 mmol) under H₂ (15 Psi), and the reaction mixturewas stirred at rt for 5 hrs. On completion, the mixture was concentratedin vacuo to give the title compound (296 mg, 910% yield) as brown oil.LC-MS (ESI⁺) m/z 339.0 (M+Na)⁺.

Step 3—3-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propylmethanesulfonate

To a mixture of2-(2,6-dioxo-3-piperidyl)-4-(3-hydroxypropyl)isoindoline-1,3-dione (296mg, 935 umol) in DCM (10 mL) was added DIPEA (362 mg, 2.81 mmol) and themixture was cooled to 0° C. MsCl (161 mg, 1.40 mmol) was added into themixture. The reaction mixture was stirred at rt for 1 hr. On completion,the mixture was poured into water (15 mL). The aqueous phase wasextracted with ethyl acetate (2×20 mL). The combined organic phase waswashed with brine (2×20 mL), then dried with anhydrous Na₂SO₄, filteredand concentrated in vacuo to give title compound (348 mg, 94% yield) asbrown oil. LC-MS (ESI⁺) m/z 395.0 (M+H)⁺.

4-[3-[4-[3-(Difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NN)

Step1—4-[3-[4-[3-(Difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propylmethanesulfonate (348 mg, 882 umol, Intermediate NM),4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine (274.36 mg, 970umol, HCl, Intermediate JP) in CH₃CN (10 mL) was added NaHCO₃ (296 mg,3.53 mmol) and the mixture was stirred at 80° C. for 12 hrs. Oncompletion, the mixture was concentrated in vacuo. The crude product waspurified by column chromatography (SiO2, Petroleum ether/Ethylacetate=0:1) to give title compound (190 mg, 30% yield) as a yellowsolid. LC-MS (ESI⁺) m/z 545.3 (M+H)⁺.

Step2—4-[3-[4-[3-(Difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of4-[3-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(20.0 mg, 36.7 umol) in THF (2 mL) was added PtO₂ (1.67 mg, 7.35 umol)under H₂ (15 Psi) and the reaction mixture was stirred at rt for 12 hrs.On completion, the mixture was concentrated in vacuo to give titlecompound (15 mg, 80% yield) as brown oil. LC-MS (ESI⁺) m/z 515.2 (M+H)⁺.

5-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]pentylmethanesulfonate (Intermediate NO)

Step1—2-(2,6-Dioxo-3-piperidyl)-5-(5-hydroxypent-1-ynyl)isoindoline-1,3-dione

A mixture of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1.00 g, 2.97 mmol, Intermediate GA), pent-4-yn-1-ol (499 mg, 5.93mmol), Pd(PPh₃)₂Cl₂ (208 mg, 296 umol), CuI (56.0 mg, 296 umol) and TEA(5.40 g, 53.3 mmol, 7.43 mL) in DMF (4 mL) was degassed and purged withN₂ gas 3 times. The mixture was stirred at 80° C. for 0.5 hr undermicrowave. On completion, the mixture was extracted with EA (2×100 mL).The organic layer was washed with brine (100 mL), dried over anhydrousNa₂SO₄, then filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography to give the title compound (900mg, 89% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14(s, 1H), 7.94-7.78 (m, 3H), 5.17 (dd, J=5.6, 12.8 Hz, 1H), 4.57 (t,J=5.2 Hz, 1H), 3.55 (q, J=6.0 Hz, 2H), 2.97-2.84 (m, 1H), 2.67-2.55 (m,4H), 2.15-2.02 (m, 1H), 1.77-1.70 (m, 2H).

Step2—2-(2,6-Dioxo-3-piperidyl)-5-(5-hydroxypentyl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(5-hydroxypent-1-ynyl)isoindoline-1,3-dione(900 mg, 2.64 mmol) in THF (20 mL) was added Pd/C (100 mg, 10 wt %) andPd(OH)₂/C (1001 mg, 10 wt %) under H₂ atmosphere (15 psi). The mixturewas stirred at rt for 2 hrs. On completion, the mixture was filtered andthe filtrate was concentrated in vacuo to give the title compound (800mg, 87% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12(s, 1H), 7.89-7.65 (m, 3H), 5.14 (dd, J=5.2, 12.8 Hz, 1H), 4.38-4.33 (m,1H), 3.43-3.34 (m, 2H), 2.89 (s, 1H), 2.78 (t, J=7.6 Hz, 2H), 2.65-2.52(m, 2H), 2.12-2.00 (m, 1H), 1.80-1.72 (m, 1H), 1.68-1.60 (m, 2H),1.48-1.41 (m, 2H), 1.35-1.24 (m, 2H).

Step 3—5-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]pentylmethanesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(5-hydroxypentyl)isoindoline-1,3-dione (200mg, 580 umol) in DCM (20 mL) was added TEA (176 mg, 1.74 mmol) and MsCl(133 mg, 1.16 mmol, 89.9 uL). The mixture was stirred at rt for 3 hrs.On completion, the mixture was washed with citric acid (10 mL), andbrine (20 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated in vauco to give the titlecompound (240 mg, 97% yield) as yellow oil. LC-MS (ESI⁺) m/z 423.3(M+1)⁺.

5-[3-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NP)

Step1—5-[5-[4-[3-(Difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]pentyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of5-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]pentylmethanesulfonate (179 mg, 424 umol, Intermediate NO) and4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine (100 mg, 354 umol,HCl, Intermediate JP) in ACN (8 mL) was added NaHCO₃ (89.2 mg, 1.06mmol) and KI (5.87 mg, 35.4 umol). The mixture was stirred at 80° C. for16 hrs. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo, the residue was purified by Pre-HPLC (acidcondition) to give the title compound (140 mg, 69% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1), 9.08 (s, 1), 7.85 (d,J=7.6 Hz, 1H), 7.79 (s, 1), 7.73 (d, J=7.2 Hz, 1H), 7.46-7.17 (m, 1H),5.14 (dd, J=5.2, 12.8 Hz, 1H), 4.38-4.27 (m, 1H), 3.03-2.95 (m, 2H),2.94-2.85 (m, 1H), 2.83-2.77 (m, 2H), 2.71-2.53 (m, 2H), 2.38-2.31 (m,2H), 2.16-1.95 (m, 7H), 1.73-1.62 (m, 2H), 1.55-1.44 (m, 2H), 1.37-1.28(m, 2H).

Step2—5-[3-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of5-[5-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]pentyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(140 mg, 244 umol) in THF (20 mL) was added PtO₂ (11.1 mg, 48.9 umol).The mixture was stirred at rt for 16 hrs under H₂ (15 psi). Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo to give the title compound (130 mg, 98% yield) as white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.85-7.83 (m, 2H), 7.78 (s,1H), 7.74-7.71 (m, 2H), 7.17 (s, 1H), 7.03-6.61 (m, 3H), 5.14 (dd,J=5.6, 12.8 Hz, 1H), 3.99-3.94 (m, 1H), 2.96-2.88 (m, 3H), 2.84-2.76 (m,2H), 2.67-2.58 (m, 2H), 2.30-2.24 (m, 2H), 1.98-1.74 (m, 7H), 1.72-1.60(m, 2H), 1.53-1.41 (m, 2H), 1.33-1.22 (m, 2H).

3-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propylMethanesulfonate (Intermediate NO)

Step1—2-(2,6-Dioxo-3-piperidyl)-5-(3-hydroxyprop-1-Ynyl)isoindoline-1,3-dione

A mixture of 5-bromo-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(1.00 g, 2.97 mmol, Intermediate GA), prop-2-yn-1-ol (333 mg, 5.93 mmol,CAS #107-19-7), Pd(PPh₃)₂Cl₂ (208 mg, 297 umol), CuI (56.5 mg, 297 umol)and TEA (5.40 g, 53.4 mmol, 7.43 mL) in DMF (4 mL) was degassed andpurged with N₂ gas 3 times, and then the mixture was stirred at 80° C.for 0.5 hr under microwave. On completion, the mixture was extractedwith EA (2×100 mL), the organic layer was washed with brine (100 mL),dried over anhydrous Na₂SO₄, then filtered and concentrated in vacuo.The residue was purified by silica gel chromatography to give the titlecompound (800 mg, 86% yield) as light white solid. H NMR (400 MHz,DMSO-d₆) δ 11.15 (s, 1H), 7.96-7.90 (m, 3H), 5.48 (t, J=6.0 Hz, 1H),5.17 (dd, J=5.2, 12.8Hz, 1H), 4.38 (d, J=6.0 Hz, 2H), 2.96-2.84 (m,11H), 2.70-2.54 (m, 2H), 2.13-2.03 (m, 1H).

Step2—2-(2,6-Dioxo-3-piperidyl)-5-(3-hydroxypropyl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(3-hydroxyprop-1-ynyl)isoindoline-1,3-dione(800 mg, 2.56 mmol) in THF (20 mL) was added Pd/C (200 mg, 10 wt %) andPd(OH)₂/C (200 mg, 10 wt %). The mixture was stirred at rt for 3 hrsunder H₂ (15 psi) atmosphere. On completion, the mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(800 mg, 98% yield) as light brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.12 (s, 1H), 7.86-7.69 (m, 3H), 5.14 (dd, J=5.2, 12.8 Hz, 1H), 4.54(t, J=5.2 Hz, 1H), 3.45-3.38 (m, 2H), 2.96-2.90 (m, 1H), 2.87-2.79 (m,2H), 2.69-2.53 (m, 2H), 2.11-2.01 (m, 1H), 1.83-1.72 (m, 2H).

Step 3—3-[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propylMethanesulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-(3-hydroxypropyl)isoindoline-1,3-dione (300mg, 948 umol) in DCM (10 mL) was added MsCl (217 mg, 1.90 mmol) and TEA(288 mg, 2.85 mmol). The mixture was stirred at rt for 3 hrs. Oncompletion, the mixture was washed with citric acid (10 mL), and brine(20 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andthe filtrate was concentrated in vauco to give the title compound (350mg, 93% yield) as yellow solid. LC-MS (ESI⁺) m/z 412.2 (M+18)⁺.

5-[3-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NR)

Step1—5-[3-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propylmethanesulfonate (167 mg, 424 umol, Intermediate NQ) and4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]piperidine (100 mg, 354 umol,HCl, Intermediate JP) in ACN (10 mL) was added NaHCO₃ (89.0 mg, 1.06mmol) and KI (5.87 mg, 35.4 umol). The mixture was stirred at 80° C. for16 hrs. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo, the residue was purified by Pre-HPLC (acidcondition) to give the title compound (100 mg, 52% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 9.09 (s, 1), 7.87-7.80(m, 1), 7.78-7.71 (m, 1H), 7.46-7.17 (m, 1H), 5.14 (dd, J=5.2, 12.8 Hz,1H), 4.38-4.28 (m, 1H), 3.00-2.93 (m, 2H), 2.91-2.79 (m, 3H), 2.65-2.53(m, 2H), 2.39-2.29 (m, 2H), 2.12-2.00 (m, 7H), 1.88-1.76 (m, 2H).

Step2—5-[3-[4-[4-Amino-3-(difluoromethyl)pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of5-[3-[4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-1-piperidyl]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(100 mg, 184 umol) in THF (15 mL) was added PtO₂ (41.7 mg, 184 umol).The mixture was stirred at rt for 16 hrs under H₂ (15 psi) atmosphere.On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (80 mg, 85% yield) aswhite solid. LC-MS (ESI⁺) m/z 515.3 (M+1)⁺.

3-[1-Oxo-4-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione(Intermediate NS)

Step 1—Tert-Butyl4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]piperidine-1-carboxylate

To a solution of 3-(4-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione(400 mg, 1.54 mmol, CAS #191732-72-6) and tert-butyl4-oxopiperidine-1-carboxylate (615 mg, 3.09 mmol) in a mixed solvent ofDCE (10 mL) and HOAc (1.05 g, 17.5 mmol) was added molecular sieves (200mg, 386 umol, 4 Å). The reaction mixture was stirred at 30° C. for 4hrs. Then, NaBH(OAc)₃ (327 mg, 1.54 mmol) was added. The resultingreaction mixture was stirred at 30° C. for 12 hrs. On completion, thereaction mixture was concentrated in vacuo to give the crude productwhich was purified by reversed-phase chromatography (0.1% FA condition)to give the title compound (168 mg, 22% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.29 (t, J=7.6 Hz, 1H), 6.95 (d,J=7.6 Hz, 1H), 6.86 (d, J=8.4 Hz, 1H), 5.35 (d, J=8.4 Hz, 1H), 5.12 (dd,J=5.2, 12.8 Hz, 1H), 4.31-4.10 (m, 2H), 3.92 (d, J=12.6 Hz, 2H),3.02-2.85 (m, 3H), 2.71-2.59 (m, 1H), 2.38-2.23 (m, 1H), 2.09-2.00 (m,1H), 1.92-1.90 (m, 2H), 1.41 (s, 9H), 1.33-1.29 (m, 2H) LC-MS (ESI⁺) m/z387.1 (M−56)⁺.

Step 2—3-[1-Oxo-4-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]piperidine-1-carboxylate(210 mg, 475 umol) in dichloromethane (10 mL) was added HCl/dioxane (4M, 5 mL). The reaction mixture was stirred at 20° C. for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (180 mg, 100% yield, HCl salt) as a white solid which wasused for the next step without purification. LC-MS (ESI⁺) m/z 343.1(M+H)⁺.

3-[4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(Intermediate NT)

Step 1—Tert-ButylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethyl]carbamate

To a solution of3-[1-oxo-4-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione (180mg, 475 umol, HCl, Intermediate NS) and tert-butylN-[2-[2-(2-oxoethoxy)ethoxy]ethyl]carbamate (176.0 mg, 712 umol,Intermediate HY) in THF (20 mL) was added KOAc (93.2 mg, 949 umol) andNaBH(OAc)₃ (111 mg, 522 umol). The reaction mixture was stirred at rtfor 36 hrs. On completion, the reaction mixture was quenched with water(1 mL) and the mixture was concentrated in vacuo. The residue waspurified by prep-HPLC (condition: 0.1% FA) to give the title compound(130 mg, 45% yield) as a colorless oil. LC-MS (ESI⁺) m/z 574.2 (M+H)⁺.1H NMR (400 MHz, DMSO-d₆) δ 11.03 (s, 1H), 7.30-7.25 (m, 1H), 6.93 (d,J=7.6 Hz, 1H), 6.82-6.75 (m, 2H), 5.33 (d, J=7.6 Hz, 1H), 5.13 (dd,J=5.2, 13.2 Hz, 1H), 4.26-4.11 (m, 2H), 4.26-4.10 (m, 1H), 3.06 (d,J=6.0 Hz, 2H), 2.99-2.89 (m, 3H), 2.68-2.59 (m, 1H), 2.30-2.26 (m, 1H),2.20-2.14 (m, 2H), 2.06-2.00 (m, 1H), 1.92-1.88 (m, 2H), 1.48-1.42 (m,2H), 1.37 (s, 9H).

Step2—3-[4-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethyl]carbamate(130 mg, 227 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL). Thereaction mixture was stirred at rt for 1 hr. On completion, the mixturewas concentrated in vacuo to give the title compound (116 mg, 99% yield,HCl salt) as a white solid. LC-MS (ESI⁺) m/z 474.2 (M+H)⁺.

4-[[1-[2-(2-Aminoethoxy)ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NU)

Step 1—Tert-ButylN-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-(4-piperidylamino)isoindoline-1,3-dione (300mg, 764 umol, HCl, Intermediate JW) and tert-butylN-[2-(2-oxoethoxy)ethyl]carbamate (233 mg, 1.15 mmol, synthesized viaStep 1 of Intermediate FS) in THF (10 mL) was added KOAc (150 mg, 1.53mmol). One hour later, NaBH(OAc)₃ (324 mg, 1.53 mmol) was added. Thereaction mixture was stirred at rt for 16 hrs. On completion, themixture was concentrated in vacuo. The residue was purified reversephase (0.1% HCl condition) to give the title compound (300 mg, 72%yield) as a white solid. LC-MS (ESI⁺) m/z 544.4 (M+H)⁺.

Step2—4-[[1-[2-(2-Aminoethoxy)ethyl]-4-piperidyl]amino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-piperidyl]ethoxy]ethyl]carbamate(300 mg, 552 umol) in DCM (5 mL) was added HCl/dioxane (10 mL). Thereaction mixture was stirred at rt for 10 hrs. On completion, themixture was concentrated in vacuo to give the title compound (240 mg,91% yield, HCl) as a yellow solid. LC-MS (ESI⁺) m/z 444.1 (M+H)⁺.

3-(5-Amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (Intermediate NV)Step 1—Methyl 2-(bromomethyl)-4-nitro-benzoate

To a solution of methyl 2-methyl-4-nitro-benzoate (3.00 g, 15.4 mmol) inCCl₄ (60.0 mL) was added NBS (3.28 g, 18.4 mmol) and BOP (68.0 mg, 154umol). The reaction mixture was stirred at 85° C. for 12 hrs. Oncompletion, the mixture was washed with saturated NaHCO₃ (20.0 mL) andbrine (50.0 mL), dried over anhydrous MgSO₄, filtered and concentratedin vacuo. The residue was purified by silica gel column chromatography(PE:AcOEt=3:1) to give the title compound (4.21 g, 100% yield) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (d, J=2.0 Hz, 1H), 8.20(dd, J=2.0, 6.4 Hz, 1H), 8.10 (d, J=6.4 Hz, 1), 4.96 (s, 2H), 4.00 (s,3H).

Step 2—3-(5-Nitro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione

To a solution of 3-aminopiperidine-2,6-dione (2.00 g, 12.2 mmol, HCl)and methyl 2-(bromomethyl)-4-nitro-benzoate (4.21 g, 15.4 mmol) in DMF(10.0 mL) was added TEA (3.07 g, 30.4 mmol). The reaction mixture wasstirred at 75° C. for 12 hrs. On completion, the reaction mixture wasdiluted with water (200 mL), filtered. The filtered cake was collected.The reaction mixture was concentrated in vacuo. The residue wastriturated EA:H₂O=1:1 (50 mL) to give the title compound (1.7 g, 48%yield) as a blue solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s, 1H), 8.53(d, J=1.2 Hz, 1H), 8.36 (dd, J=2.0, 8.4 Hz, 1), 7.98 (d, J=8.4 Hz, 1H),5.17 (dd, J=5.2, 13.2 Hz, 1H), 4.69-4.45 (m, 1H), 3.01-2.86 (m, 1H),2.68-2.59 (m, 1H), 2.48-2.35 (m, 1H), 2.13-2.02 (m, 1H).

Step 3—3-(5-Amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione

To a solution of 3-(5-nitro-1-oxo-isoindolin-2-yl)piperidine-2,6-dione(500 mg, 1.73 mmol) in a mixed of solvent DMF (5.00 mL) and THF (10.0mL) was added Pd/C (50.0 mg, 1.73 mmol, 10% wt) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred under H₂ (15 psi) at rt for 12 hours. On completion, thereaction mixture was filtered and the filter cake was collected anddried in vacuo to give the title compound (530 mg, 82% yield) as a brownsolid. LC-MS (ESI⁺) m/z 260.2 (M+H)⁺.

3-[1-Oxo-5-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione(Intermediate NW)

Step 1—Tert-Butyl4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]piperidine-1-carboxylate

To a solution of 3-(5-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione(448 mg, 1.73 mmol, Intermediate NV) and tert-butyl4-oxopiperidine-1-carboxylate (689 mg, 3.46 mmol) in a mixed solvent ofDCE (10 mL) and HOAc (1.18 g, 19.6 mmol) was added molecular sieves (200mg, 386 umol, 4Å). The reaction mixture was stirred at 30° C. for 4 hrs.Then, NaBH(OAc)₃ (366 mg, 1.73 mmol) was added. The resulting reactionmixture was stirred at 30° C. for 12 hrs. On completion, the reactionmixture was concentrated in vacuo to give the crude product, which waspurified by reversed-phase chromatography (0.1% FA condition) to givethe title compound (120 mg, 15% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.93 (s, 1), 7.39 (d, J=8.8 Hz, 1), 7.26-7.17 (m, 1H),6.69 (s, 1), 6.28 (d, J=8.8 Hz, 1H), 5.02 (dd, J=5.2, 13.2 Hz, 1),4.34-4.10 (m, 2H), 3.89 (d, J=12.4 Hz, 2H), 3.06-2.82 (m, 3H), 2.71-2.55(m, 1), 2.41-2.29 (m, 1), 1.95-1.93 (m, 1), 1.92-1.89 (m, 2H), 1.41 (s,9H), 1.27-1.24 (m, 2H); LC-MS (ESI⁺) m/z 443.1 (M+H)⁺.

Step 2—3-[1-Oxo-5-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]piperidine-1-carboxylate(120 mg, 257.6 umol) in DCM (5.00 mL) was added HCl/dioxane (4.00 M,2.83 mL). The reaction mixture was stirred at rt for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (97.6 mg, 100% yield, HCl) as a white solid. LC-MS (ESI⁺)m/z 343.1 (M+H)⁺.

3-[5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (Intermediate NX)

Step 1—Tert-ButylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethyl]carbamate

To a solution of3-[1-oxo-5-(4-piperidylamino)isoindolin-2-yl]piperidine-2,6-dione (97.0mg, 256 umol, HCl, Intermediate NW) and2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (82.3mg, 333 umol, synthesized via Steps 1-2 of Intermediate IB) in a mixedof solvent DMF (3.00 mL) and DCM (20.0 mL) was added KOAc (50.3 mg, 512umol) and NaBH(OAc)₃ (81.4 mg, 384 umol). The reaction mixture wasstirred at rt for 12 hrs. On completion, the reaction mixture wasquenched with water (1.00 mL) and the mixture was concentrated in vacuo.The residue was purified by prep-HPLC (condition: 0.1% FA) to give thetitle compound (60 mg, 33% yield) as a colorless oil. LC-MS (ESI⁺) m/z574.2 (M+H)⁺.

Step2—3-[5-[[1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-4-piperidyl]amino]-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[2-[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]amino]-1-piperidyl]ethoxy]ethoxy]ethyl]carbamate(60 mg, 105 umol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 5.00mL). The reaction mixture was stirred at rt for 1 hr. On completion, themixture was concentrated in vacuo to give the title compound (53 mg, 99%yield, HCl) as a white solid. LC-MS (ESI⁺) m/z 474.2 (M+H)⁺.

Tert-butylN-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]piperazin-1-yl]ethoxy]ethyl]carbamate(Intermediate NY)

To a solution of2-(2,6-dioxo-3-piperidyl)-4-piperazin-1-yl-isoindoline-1,3-dione (0.5 g,1.46 mmol, HCl, synthesized via Steps 1-2 Intermediate IA) andtert-butyl N-[2-(2-oxoethoxy)ethyl]carbamate (445 mg, 2.19 mmol,synthesized via Step 1 of Intermediate FS) in THF (10 mL) was added Et₃N(296 mg, 2.92 mmol, 407 uL) and AcOH (263 mg, 4.38 mmol, 251 uL) andthen was added NaBH(OAc)₃ (619 mg, 2.92 mmol). The mixture was stirredat rt for 6 hr. On completion, the mixture was concentrated in vacuo.The crude product was purified by reversed-phase chromatography (0.1%HCl condition) to give the title compound (0.3 g, crude) as a yellowsolid. LC-MS (ESI⁺) m/z 530.4 (M+H)⁺.

5-[4-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate NZ)

Step 1—Tert-ButylN-[2-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

A mixture of2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (390mg, 1.03 mmol, HCl, synthesized via Steps 1-2 of Intermediate IB),tert-butyl N-[2-[2-[2-(2-oxoethoxy)ethoxy]ethoxy]ethyl]carbamate (250mg, 858 umol, Intermediate JX), TEA (86.8 mg, 858 umol) in THF (10 mL)was added HOAc (51.5 mg, 858 umol, 49.0 uL) and NaBH(OAc)₃ (363 mg, 1.72mmol), the mixture was stirred at rt for 72 hrs under N₂ atmosphere. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by Pre-HPLC (0.1% FA condition) to give the title compound (220mg, 41% yield) as yellow solid. LC-MS (ESI⁺) m/z 618.4 (M+H)⁺.

Step2—5-[4-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (220 mg, 356 umol)in THF (10 mL) was added HCl/dioxane (4 M, 5 mL). The mixture wasstirred at rt for 3 hrs. On completion, the mixture was concentrated invacuo to give the title compound (190 mg, 96% yield) as yellow solid.LC-MS (ESI⁺) m/z 518.3 (M+H)⁺.

5-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate OA)

Step 1—Tert-ButylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-5-piperazin-1-yl-isoindoline-1,3-dione (250mg, 730 umol, HCl, synthesized via Steps 1-2 of Intermediate IB) andtert-butyl (2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (271 mg, 1.10 mmol,Intermediate HY) in THF (20.0 mL) was added KOAc (143 mg, 1.46 mmol) andNaBH(OAc)₃ (170 mg, 803 umol). The reaction mixture was stirred at rtfor 3 hrs. On completion, the reaction mixture was quenched with water(1.00 mL). The mixture was concentrated in vacuo. The residue waspurified by prep-HPLC (condition: 0.1% FA) to give the title compound(275 mg, 62% yield) as a yellow solid. LC-MS (ESI⁺) m/z 574.2 (M+H)⁺.

Step2—5-[4-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]piperazin-1-yl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[4-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamate(275 mg, 455 umol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 7.60mL). The reaction mixture was stirred at rt for 1 hr. On completion, themixture was concentrated in vacuo to give the title compound (232 mg,99% yield, HCl) as a yellow solid. LC-MS (ESI⁺) m/z 474.3 (M+H)⁺.

[(3R,5S)-5-[[4-[4-[[2-[2-(Cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]acetate(Intermediate OB)

Step 1—Tert-Butyl(2S,4R)-4-acetoxy-2-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate

To a solution of tert-butyl(2S,4R)-2-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-4-hydroxy-pyrrolidine-1-carboxylate(180 mg, 227 umol, synthesized via Steps 1-3 of Intermediate KG) inpyridine (5.00 mL) was added acetyl acetate (545 mg, 5.34 mmol). Thereaction mixture was stirred at rt for 12 hrs. On completion, thereaction mixture was concentrated in vacuo. The crude product waspurified by prep-HPLC (0.1%, HCl) to give the title compound (180 mg,95% yield) as colorless oil. LC-MS (ESI⁺) m/z 835.1 (M+H)⁺.

Step2—[(3R,5S)-5-[[4-[4-[[2-[2-(Cyclopropylmetylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]acetate

To a solution of tert-butyl(2S,4R)-4-acetoxy-2-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidine-1-carboxylate(110 mg, 132 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 7.33mL). The reaction mixture was stirred at rt for 1 hr. On completion, thereaction mixture was concentrated in vacuo to give the title compound(88.4 mg, 100% yield) as a white solid. LC-MS (ESI⁺) m/z 635.2 (M+H)⁺.

[(3R,5S)-1-[(2S)-2-Amino-3,3-dimethyl-butanoyl]-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]acetate(Intermediate OC)

Step1—[(3R,5S)-1-[(2S)-2-(Tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]acetate

To a solution of[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]acetate (88.4 mg, 132 umol, Intermediate OB) and(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoic acid (36.6 mg,158 umol, CAS #62965-35-9) in DMF (3.00 mL) was added DIPEA (85.1 mg,659 umol), The reaction mixture was stirred at rt for 0.5 hr. After,HATU (60.10 mg, 158.07 umol) was added. The resulting reaction mixturewas stirred at rt for 0.5 hr. On completion, the reaction mixture wasquenched with water (15.0 mL), and extracted with ethyl acetate (3×30mL). The combined organic layer was washed with brine (20 mL), driedover anhydrous sulfate sodium, filtered and concentrated in vacuo togive the title compound (110 mg, 99% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 8.74 (s, 1H), 8.30 (s, 1H), 8.17 (d,J=5.2 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.24 (s,1H), 7.13 (d, J=5.2 Hz, 1H), 7.05-6.73 (m, 2H), 5.28 (s, 1H), 5.06 (d,J=10.0 Hz, 1H), 4.68 (t, J=7.6 Hz, 1H), 4.51 (dd, J=6.4, 16 Hz, 1H),4.28 (dd, J=5.2, 14.9 Hz, 1H), 4.11 (d, J=10.0 Hz, 1H), 4.00-3.98 (m,1H), 3.68-3.61 (m, 1H), 3.17 (dd, J=5.2, 6.8 Hz, 2H), 2.76-2.68 (m, 1H),1.98 (s, 3H), 1.34 (s, 9H), 1.08 (s, 1H), 0.83 (s, 9H), 0.57-0.50 (m,2H), 0.28-0.22 (m, 2H). LC-MS (ESI⁺) m/z 848.3 (M+H)⁺.

Step2—[(3R,5S)-1-[(2S)-2-Amino-3,3-dimethyl-butanoyl]-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]acetate

To a solution of[(3R,5S)-1-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]-5-[[4—[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]pyrrolidin-3-yl]acetate (110 mg, 130 umol) in DCM (5.00 mL) was added HCl/dioxane (4.00M, 5.45 mL). The reaction mixture was stirred at rt for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (100 mg, 98% yield) as a white solid. LC-MS (ESI⁺) m/z748.2 (M+H)⁺.

3-[5-[4-(4-aminobutoxy)butyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate OD)

Step 1—Tert-butylN-[4-([4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]but-3-yn-1-yl]oxy)butyl]carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione(2 g, 6 mmol, Intermediate HN) in DMSO (20 mL) were added tert-butylN-[4-(but-3-yn-1-yloxy)butyl]carbamate (4.3 g, 18 mmol, IntermediateOI), Pd(PPh₃)₄ (683.4 mg, 0.59 mmol), CuI (225.3 mg, 1.18 mmol) and TEA(10 mL) at rt under nitrogen atmosphere. The resulting mixture wasstirred for 16 h at 85° C. under nitrogen atmosphere. The reactionmixture was cooled to rt and concentrated under reduced pressure toremove the TEA. The resulting mixture was diluted with ice/water (50 ml,plus 3 ml AcOH) and extracted with EtOAc (2×50 mL). The combined organiclayer was washed with brine (30 mL) and dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by reverse phase flash chromatography with thefollowing conditions: Column: WelFlash™ C18-1, 20-40 μm, 330 g; EluentA: Water (plus 10 mmol/L FA); Eluent B: ACN; Gradient: 5% B-5% B in 10min; 50% B-60% B in 25 min; Flow rate: 80 mL/min; Detector: 220/254 nm;desired fractions were collected at 57% B and concentrated under reducedpressure to afford tert-butylN-[4-([4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]but-3-yn-1-yl]oxy)butyl]carbamate(1.5 g, 51%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s,1H), 7.24 (s, 1H), 7.10 (s, 2H), 6.79 (s, 1H), 5.41-5.34 (m, 1H), 3.55(t, J=6.8 Hz, 2H), 3.44 (t, J=6.3 Hz, 2H), 3.32 (s, 3H), 2.96-2.88 (m,3H), 2.71-2.65 (m, 4H), 2.11-2.00 (m, 1H), 1.49 (s, 2H), 1.48-1.40 (m,2H), 1.37 (s, 9H); LC/MS (ESI, m/z): [M−1]⁻=497.2.

Step 2—Tert-butylN-(4-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]butoxy]butyl)carbamate

To a solution of tert-butylN-[4-([4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]but-3-yn-1-yl]oxy)butyl]carbamate(1.5 g, 3.01 mmol) in THF (50 mL) was added palladium on charcoal (0.15g, 10% w/w) under nitrogen atmosphere. The mixture was hydrogenated atrt for 4 h using a hydrogen balloon. The resulting mixture was filteredthrough a celite pad and concentrated under reduced pressure to affordtert-butylN-(4-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]butoxy]butyl)carbamate(1.2 g, 79%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (br s,1H), 6.94-6.89 (m, 1H), 6.87 (d, J=1.5 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H),5.23 (dd, J=12.5, 5.4 Hz, 1H), 4.73-4.60 (m, 1H), 3.49-3.36 (m, 7H),3.15 (d, J=6.1 Hz, 2H), 2.97 (d, J=16.7 Hz, 1H), 2.87 (dd, J=13.3, 5.0Hz, 1H), 2.70 (t, J=7.6 Hz, 2H), 2.32-2.19 (m, 1H), 1.76-1.50 (m, 9H),1.46 (s, 9H); LC/MS (ESI, m/z): [M+1]⁺=503.4.

Step3—3-[5-[4-(4-Aminobutoxy)butyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride

A solution of tert-butylN-(4-[4-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-5-yl]butoxy]butyl)carbamate(150 mg, 0.29 mmol) in dioxane (2 mL) was treated with a solution of HCl(gas) in 1,4-dioxane (4 M, 2 mL) for 16 h at rt under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure to afford3-[5-[4-(4-aminobutoxy)butyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl]piperidine-2,6-dionehydrochloride (100 mg, 77%) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 7.86 (br s, 3H), 7.05-6.98 (m, 2H), 6.87 (d,J=8.0 Hz, 1H), 5.35 (dd, J=12.7, 5.3 Hz, 1H), 3.74-3.63 (m, 1H), 3.57(s, 1H), 3.49 (dd, J=11.6, 4.4 Hz, 1H), 3.42-3.33 (m, 4H), 2.97-2.85 (m,1H), 2.82-2.59 (m, 6H), 2.06-1.96 (m, 1H), 1.67-1.48 (m, 8H); LC/MS(ESI, m/z): [(M+1)]⁺=403.2.

(S)-7-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide(Intermediate OE)

(S)-7-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-2-((S)-2-(2-methoxyacetamido)-3,3-dimethylbutanoyl)-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamidewas synthesized as described for Intermediate LY, using2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl4-methylbenzenesulfonate, Intermediate 00, as the tosylate in Step 1 tocouple with alcohol Intermediate MH. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37(br. s., 1H), 8.17-8.23 (m, 1H), 7.30-7.46 (m, 1H), 6.77-7.14 (m, 7H),4.63-5.11 (m, 5H), 4.03-4.10 (m, 2H), 3.70-3.92 (m, 4H), 3.40-3.63 (m,18H), 3.28-3.35 (m, 3H), 2.91-3.08 (m, 2H), 2.78-2.88 (m, 2H), 2.61-2.76(m, 2H), 1.52-1.88 (m, 4H), 0.84-1.04 (m, 9H). LC-MS (ESI⁺): m/z 771.2(M+H)⁺.

2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-oicacid (Intermediate OF)

Step1—2-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)isoindoline-1,3-dione

To a stirred solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (10g, 35.4 mmol, CAS #2615-15-8) in THF (200 ml) was added phtalimide(6.253 g, 42.51 mmol), and PPh₃ (12.06 g, 46.02 mmol) at roomtemperature. The reaction mixture was degassed and purged with nitrogenseveral times. The reaction mixture was cooled to 0° C. then DEAD (8.02g, 46.02 mmol) was added dropwise to the reaction mixture at 0° C. Afterthe addition, the mixture was stirred at room temperature for 12 h. Themixture was concentrated in vacuo and the residue was purified viacolumn chromatography (DCM/MeOH=0%-10%) to give the desired compound(6.4 g, 44.0%) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 7.93-7.81(m, 4H), 4.57 (t, J=5.5 Hz, 1H), 3.75 (t, J=5.8 Hz, 2H), 3.63 (t, J=5.8Hz, 2H), 3.54-3.48 (m, 7H), 3.46 (ddd, J=7.0, 4.7, 1.9 Hz, 7H),3.43-3.38 (m, 6H).

Step 2—Tert-Butyl20-(1,3-dioxoisoindolin-2-yl)-3,6,9,12,15,18-hexaoxaicosan-1-oate

To a solution of2-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)isoindoline-1,3-dione (7.0g, 17.03 mmol) in THF (200 mL) was added 60% NaH (885.6 mg, 22.14 mmol)at 0° C. After stirring for 0.5 h at 0° C., tert-butyl 2-bromoacetate(4.65 g, 23.84 mmol) was added dropwise to the reaction mixture at 0° C.The reaction mixture was stirred at 0° C. for 2 hrs, then warmed to rtwith stirring on for another 2 hrs. The reaction mixture was quenchedwith water at 0° C., and extracted with EtOAc (100 mL×2). The combinedorganic layer was washed with brine (50 mL×3), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bycolumn chromatography (DCM/MeOH=0%-10%) to give the desired compound(4.5 g, 50.3%) as a pale yellow solid. LC-MS (ESI⁺): m/z 526.3 (M+H)⁺.

Step 3—20-(1,3-dioxoisoindolin-2-yl)-3,6,9,12,15,18-hexaoxaicosan-1-oicAcid

To a solution of tert-butyl20-(1,3-dioxoisoindolin-2-yl)-3,6,9,12,15,18-hexaoxaicosan-1-oate (4.5g, 8.571 mmol) in DCM (100 mL) was added TFA (50 mL) at rt. The reactionmixture was stirred at rt for 2 hs, then concentrated in vacuo to givethe desired compound (3.5 g, 87.1%) as a yellow solid. LC-MS (ESI⁺): m/z470.2 (M+H)⁺.

Step 4:2,2-dimethyl-4-oxo-3,8,11,14,17,20,23-heptaoxa-5-azapentacosan-25-oicAcid

To a solution of20-(1,3-dioxoisoindolin-2-yl)-3,6,9,12,15,18-hexaoxaicosan-1-oic acid(3.5 g, 7.463 mmol) in EtOH (50 mL) was added hydrazinium (716.8 mg,22.4 mmol, 99%) at r.t. The reaction mixture was heated to reflux for 3hs. A white solid formed, then the reaction mixture was filtered and thefiltrate was concentrated in vacuo. The residue was dissolved in CH₃CN(100 mL). (Boc)₂O (9.8 g, 44.8 mmol) was added to the reaction mixtureat rt and the mixture was stirred at room temperature for 2 hr. Thereaction mixture was then concentrated in vacuo to give a residue whichwas purified by column chromatography (DCM/MeOH=0%-10%) to give thedesired compound (1.4 g, 42.7%) as a colorless oil. LC-MS (ESI⁺): m/z440.5 (M+H)⁺.

Tert-ButylN-[3-[2,2-dimethyl-3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate(Intermediate OG)

Step1—2-[3-(3-Hydroxy-2,2-dimethylpropoxy)propyl]-2,3-dihydro-1H-isoindole-1,3-dione

To a solution of 2,2-dimethylpropane-1,3-diol (38.8 g, 373 mmol, CAS#126-30-7) in DMF (400 mL) was added sodium hydride (60% dispersion inmineral oil, 15.0 g, 375 mmol) at 0° C. The mixture was stirred for 15min at the same temperature. Then a solution of2-(3-bromopropyl)-2,3-dihydro-1H-isoindole-1,3-dione (50 g, 187 mmol,CAS #5460-29-7) in DMF (50 mL) was added dropwise and the mixture wasallowed to warm to room temperature and stirred for 16 hours. Thereaction was quenched by the addition of a solution of HOAc (60 g) inwater (1 L) at rt. The resulting mixture was extracted with EtOAc (3×500mL). The combined organic layer was washed with brine (500 mL) and driedover anhydrous Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography, eluted with 50% ethyl acetate in petroleum ether toafford2-[3-(3-hydroxy-2,2-dimethylpropoxy)propyl]-2,3-dihydro-1H-isoindole-1,3-dione(7.4 g, 11%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.81(dd, J=5.5, 3.1 Hz, 2H), 7.69 (dd, J=5.5, 3.1 Hz, 2H), 3.77 (t, J=6.6Hz, 2H), 3.44-3.37 (m, 4H), 3.20 (s, 2H), 1.92 (p, J=6.2 Hz, 2H), 0.86(s, 6H); LC/MS (ESI, m/z): [(M+18)]⁺=292.30.

Step 2—Tert-Butyl N-[3-(3-hydroxy-2,2-dimethylpropoxy)propyl]carbamate

To a stirred solution of2-[3-(3-hydroxy-2,2-dimethylpropoxy)propyl]-2,3-dihydro-1H-isoindole-1,3-dione(6.1 g, 20.9 mmol) in EtOH (400 mL) was added hydrazine hydrate (2.1 g,41.9 mmol, 98%) at rt under nitrogen atmosphere. The resulting solutionwas stirred for 2 h at 70° C. The mixture was cooled down to roomtemperature. To the above mixture was added di-tert-butyl dicarbonate(27.4 g, 125.6 mmol) at rt and the resulting mixture was stirred foradditional 16 hours at rt. After filtration, the filter cake was washedwith EtOH (50 mL) and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with 25% ethyl acetate in petroleum ether, to afford tert-butylN-[3-(3-hydroxy-2,2-dimethylpropoxy)propyl]carbamate (5.6 g, 82%) as alight yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.00 (br s, 1H), 3.45 (td,J=5.8, 1.3 Hz, 2H), 3.40 (t, J=2.0 Hz, 2H), 3.25-3.14 (m, 4H), 1.71 (p,J=6.6, 6.1 Hz, 2H), 1.41 (s, 9H), 0.87 (s, 6H); LC/MS (ESI, m/z):[(M−100+1)]⁺=162.35.

Step 3—Tert-ButylN-[3-[2,2-dimethyl-3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate

To a solution of tert-butylN-[3-(3-hydroxy-2,2-dimethylpropoxy)propyl]carbamate (5.6 g, 21.4 mmol)in DMF (60 mL) was added sodium hydride (60% dispersion in mineral oil,1.7 g, 42.5 mmol) at 0° C. The mixture was stirred for 15 min at thesame temperature. Then a solution of 3-bromoprop-1-yne (2.5 g, 21.43mmol) in DMF (20 mL) was added dropwise and the mixture was allowed towarm to rt and stirred for 16 hours. The reaction was quenched by theaddition of saturated aqueous NH₄Cl (300 mL) at room temperature. Theresulting mixture was diluted with water (200 mL) and extracted withEtOAc (3×200 mL). The combined organic layers was washed with brine (500mL) and dried over anhydrous Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with 10% ethyl acetate in petroleumether, to afford tert-butylN-[3-[2,2-dimethyl-3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (2.9 g,45%) as a light yellow oil: ¹H NMR (400 MHz, DMSO-d₆) δ 6.71 (t, J=5.7Hz, 1H), 4.10 (d, J=2.4 Hz, 2H), 3.41-3.31 (m, 3H), 3.20 (s, 2H), 3.10(s, 2H), 2.98 (q, J=6.6 Hz, 2H), 1.61 (p, J=6.6 Hz, 2H), 1.38 (s, 9H),0.84 (s, 6H); LC/MS (ESI, m/z): [(M+1)]⁺=300.20.

Tert-Butyl N-[3-(prop-2-yn-1-yloxy)propyl]carbamate (Intermediate OH)

A solution of tert-butyl N-(3-hydroxypropyl)carbamate (1 g, 6 mmol, CAS#58885-58-8) in THF (40 mL) was treated with NaH (60% dispersion inmineral oil, 0.3 g, 14 mmol) for 30 min at 0° C. under nitrogenatmosphere. Next, a solution of 3-bromoprop-1-yne (0.7 g, 6.28 mmol) inTHF (5 mL) was added dropwise at 0° C. The resulting mixture was stirredfor 16 h at rt. The reaction was quenched with saturated aqueous NH₄HCO₃(100 mL) and extracted with EtOAc (3×50 mL). The combined organic layerwas washed with brine (50 mL) and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with5%-20% ethyl acetate in petroleum ether, to afford tert-butylN-[3-(prop-2-yn-1-yloxy)propyl]carbamate (0.6 g, 49%) as a yellow oil:¹H NMR (400 MHz, DMSO-d₆) δ 6.77 (t, J=5.7 Hz, 1H), 4.10 (t, J=2.0 Hz,2H), 3.44-3.39 (m, 3H), 2.99-2.91 (m, 2H), 1.64-1.59 (m, 2H), 1.38 (s,9H); LC/MS (ESI, m/z): [(M−1)]⁻212.2.

Tert-Butyl N-[4-(but-3-yn-1-yloxy)butyl]carbamate (Intermediate OI)

Step 1—4-(4-Bromobutoxy)but-1-yne

To a stirred solution of 1,4-dibromobutane (201 g, 933 mmol) in acetone(1 L) were added Cs₂CO₃ (223 g, 685 mmol) and but-3-yn-1-ol (43.6 g,622.05 mmol) at rt. The resulting mixture was stirred for 16 h at rtunder nitrogen atmosphere. After filtration, the filter cake was washedwith acetone (2×50 mL). The filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with 1% ethyl acetate in petroleum ether to afford4-(4-bromobutoxy)but-1-yne (29 g, 23%) as a light yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 3.54 (t, J=6.9 Hz, 2H), 3.49 (t, J=6.2 Hz, 2H), 3.44(t, J=6.6 Hz, 2H), 2.45 (td, J=7.0, 2.6 Hz, 2H), 2.02-1.88 (m, 3H),1.80-1.65 (m, 2H).

Step 2—4-(4-Azidobutoxy)but-1-yne

A mixture of 4-(4-bromobutoxy)but-1-yne (29 g, 141 mmol) and NaN₃ (14 g,212 mmol) in DMSO (300 mL) was stirred for 4 h at rt under nitrogenatmosphere. The resulting mixture was diluted with ice water (1 L) andextracted with petroleum ether/EtOAc (5/1, v/v, 2×500 mL). The combinedorganic layers was washed with brine (500 mL) and dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure to afford 4-(4-azidobutoxy)but-1-yne (22.2 g, 94%) as a lightyellow oil: ¹H NMR (400 MHz, CDCl₃) δ 3.53 (td, J=6.9, 1.6 Hz, 2H), 3.47(td, J=6.0, 1.7 Hz, 2H), 3.29 (t, J=6.2 Hz, 2H), 2.44 (tt, J=7.0, 2.2Hz, 2H), 1.97 (t, J=2.7 Hz, 1H), 1.73-1.57 (m, 4H); LC/MS (ESI, m/z):[(2M+1)]⁺=335.25.

Step 3—4-(But-3-yn-1-yloxy)butan-1-amine

A solution of 4-(4-azidobutoxy)but-1-yne (22.2 g, 132.8 mmol) and Ph₃P(52.2 g, 199.2 mmol) in THF (400 mL) and H₂O (80 mL) was stirred for 4 hat 50° C. under nitrogen atmosphere. The resulting mixture was cooledand concentrated under reduced pressure to remove THF. The residue wasacidified to pH=1 with 4 M aqueous HCl. The resulting mixture wasextracted with EtOAc (2×500 mL). The water layer was neutralized to pH=7with 2 M aqueous NaOH, and extracted with DCM (2×500 mL). The combinedorganic layers was washed with brine (500 mL) and dried over anhydrousNa₂SO₄. After filtration, the filtrate was concentrated under reducedpressure to afford crude product (18 g). LC/MS (ESI, m/z):[(M+1)]⁺=142.1.

Step 4—Tert-Butyl N-[4-(but-3-yn-1-yloxy)butyl]carbamate

To a stirred solution of 4-(but-3-yn-1-yloxy)butan-1-amine (18 g, 127.5mmol) in DCM (500 mL) and H₂O (500 mL) were added NaHCO₃ (21.4 g, 254.9mmol) and Boc₂O (33.4 g, 152.9 mmol) at rt. The resulting mixture wasstirred for 16 h at rt under nitrogen atmosphere. The resulting mixturewas extracted with CH₂Cl₂ (2×500 mL). The combined organic layers waswashed with brine (500 mL) and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with20% ethyl acetate in petroleum ether to afford tert-butylN-[4-(but-3-yn-1-yloxy)butyl]carbamate (30 g, 98%) as a light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 4.67 (s, 1H), 3.54 (td, J=6.9, 3.6 Hz,2H), 3.51-3.42 (m, 2H), 3.13 (q, J=5.6, 4.7 Hz, 2H), 2.45 (dh, J=7.2,4.0, 3.5 Hz, 2H), 1.98 (q, J=2.8 Hz, 1H), 1.58 (td, J=8.7, 7.7, 4.4 Hz,4H), 1.42 (s, 9H); LC/MS (ESI, m/z): [(M+1)]⁺=242.3.

Tert-Butyl N-[3-[3-(prop-2-yn-1-yloxyl)propoxy]propyl](Intermediate OJ)

Step 1—tert-butyl N-[3-(methanesulfonyloxy)propyl]carbamate

To a stirred solution of tert-butyl N-(3-hydroxypropyl)carbamate (92.6g, 528.4 mmol, CAS #58885-58-8) in DCM (800 mL) were added TEA (80.2 g,792.7 mmol) and a solution of MsCl (60.5 g, 528.5 mmol) in DCM (200 mL)dropwise at 0° C. over 30 min under nitrogen atmosphere. The resultingmixture was stirred for 30 min at rt under nitrogen atmosphere. Theresulting mixture was diluted with water (2 L) and extracted with CH₂Cl₂(3×800 mL). The combined organic layers was washed with brine (1 L) anddried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with 40% ethyl acetate in petroleumether to afford tert-butyl N-[3-(methanesulfonyloxy)propyl]carbamate(112 g, 84%) as a light brown solid. ¹H NMR (400 MHz, CDCl₃) δ 4.91 (brs, 1H), 4.24 (td, J=6.9, 6.4, 2.9 Hz, 2H), 3.21 (d, J=7.9 Hz, 2H),3.06-2.92 (m, 3H), 1.89 (pd, J=6.3, 2.6 Hz, 2H), 1.39 (d, J=3.0 Hz, 9H).

Step 2—tert-butyl N-[3-(3-hydroxypropoxy)propyl]carbamate

To a solution of propane-1,3-diol (50 g, 657 mmol) in DMF (500 mL) wasadded sodium hydride (4.79 g, 200 mmol, 60% dispersed in mineral oil) at0° C. The mixture was stirred for 15 min at rt. To the above mixture wasadded a solution of tert-butyl N-[3-(methanesulfonyloxy)propyl]carbamate(25.3 g, 100 mmol) in DMF (150 mL) dropwise rt and the mixture wasstirred for 16 hours at rt. The reaction was quenched with sat. NH₄Cl(200 mL) at 0° C. The resulting mixture was concentrated under reducedpressure. The residue was diluted with brine (1.5 L) and extracted withEtOAc (3×500 mL). The combined organic layers was washed with brine (500mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, eluted with 30% ethyl acetate in petroleumether to afford tert-butyl N-[3-(3-hydroxypropoxy)propyl]carbamate (13.7g, 59%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.11 (s, 1H),3.57 (td, J=6.3, 1.9 Hz, 2H), 3.50-3.42 (m, 4H), 3.19 (q, J=6.5 Hz, 2H),1.88-1.78 (m, 2H), 1.71 (p, J=6.5 Hz, 2H), 1.41 (s, 9H); LC/MS (ESI,m/z): [(M+1)]⁺=234.15.

Step 3—Tert-Butyl N-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate

To a solution of tert-butyl N-[3-(3-hydroxypropoxy)propyl]carbamate(12.5 g, 53.6 mmol) in THF (300 mL) was added sodium hydride (2.6 g,108.3 mmol, 60% dispersion in mineral oil) at 0° C. The mixture wasstirred for 15 min. To the mixture was added a solution of3-bromoprop-1-yne (6.4 g, 53.8 mmol) in THF (50 mL) dropwise and themixture was warmed to rt and stirred for 16 hours. The reaction wasquenched with sat. NH₄Cl (200 mL) at 0° C., diluted with brine (500 mL)and extracted with EtOAc (3×300 mL). The combined organic layers waswashed with brine (500 mL) and dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography, eluted with25% ethyl acetate in petroleum ether to afford tert-butylN-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (9.2 g, 60%) as alight yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.90 (br s, 1H), 4.11 (d,J=2.4 Hz, 2H), 3.57 (t, J=6.3 Hz, 2H), 3.50-3.40 (m, 4H), 3.18 (t, J=7.2Hz, 2H), 2.42 (t, J=2.4 Hz, 1H), 1.83 (p, J=6.2 Hz, 2H), 1.71 (p, J=6.2Hz, 2H), 1.41 (s, 9H).

4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate OK)

4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dionewas synthesized as described in Steps 1-2 of Example 127.

2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]aceticAcid (Intermediate OL)

2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]aceticacid was synthesized via Steps 1-2 of Example 152.

2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicAcid (Intermediate OM)

2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid was synthesized via Steps 1-4 of Intermediate DF.

2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl4-methylbenzenesulfonate (Intermediate ON)

Step 1—3,6,9,12-tetraoxatetradecane-1,14-diylbis(4-methylbenzenesulfonate)

To a mixture of 3,6,9,12-tetraoxatetradecane-1,14-diol (10 g, 42 mmol,CAS #75506-78-4) and TsCl (17.56 g, 92.4 mmol) in DCM (200 ml) was addedTEA (17 g, 168 mmol) dropwise at rt and the mixture was stirred at rtovernight. Then the reaction mixture was concentrated in vacuo, theresidue was dissolved in EtOAc (100 ml) and washed with water (100ml×2), brine (100 ml), dried with Na₂SO₄, and filtered. The organicphase was evaporated and the residue was purified by silica gelchromatography (PE: EA=1:1) to give the title compound (19.17 g, 83.35yield) as a yellow solid LC-MS (ESI⁺): m/z 547.1 (M+H)⁺.

Step 2—3,6,9,12-tetraoxatetradecane-1,14-diylbis(4-methylbenzenesulfonate)

To a solution of 3,6,9,12-tetraoxatetradecane-1,14-diylbis(4-methylbenzenesulfonate) (19.17 g, 35.1 mmol) in DMF (100 ml) wasadded NaN₃ (2.51 g, 38.62 mmol). The mixture was stirred rt for 2 days.The mixture was poured into water (300 ml) and extracted with EtOAc(3×300 ml). The combined organic layers were washed with water (300ml×3) and brine (300 ml), dried with Na₂SO₄, and filtered. The organicphase was evaporated and the residue was purified by silica gelchromatography (PE:EA) to give the title compound as a colorless oil(6.5 g, 44% yield). LC-MS (ESI⁺): m/z 418.2 (M+H)⁺.

Step 3—2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl4-methylbenzenesulfonate

A mixture of 14-azido-3,6,9,12-tetraoxatetradecyl4-methylbenzenesulfonate (10 g, 20.4 mmol), Pd/C (20%, 1 g), (Boc)₂O(6.7 g, 30.6 mmol) and MeOH (200 mL) was stirred for overnight at rtunder H₂. The mixture was filtered and concentrated in vacuo. To themixture was added H₂O (200 mL) then it was extracted with EA (300 mL).The organic layer was concentrated and purified by column chromatography(PE/EA=2/1 to 1/1 to EA) to give2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl4-methylbenzenesulfonate (8.2 g, 69% yield) as a yellow oil. ¹H NMR (400MHz, CDCl₃) δ 7.81-7.79 (d, J=8 Hz, 2H), 7.35-7.33 (d, J=8 Hz, 2H),4.17-4.13 (t, J=4.8 Hz, 2H), 3.70-3.47 (m, 16H), 3.31-3.29 (t, J=5.2 Hz,2H), 2.45 (s, 3H), 1.44 (s, 9H). LC-MS (ESI⁺): m/z 492.7 (M+H)⁺.

2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl4-methylbenzenesulfonate (Intermediate OO)

Step 1—Tert-Butyl Tert-Butyl(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)carbamate

To a stirred solution of 17-amino-3,6,9,12,15-pentaoxaheptadecan-1-ol(4.0 g, 14.22 mmol, CAS #39160-70-8) in THF (50 mL) was added (Boc)₂O(3.72 g, 17.06 mmol) and NaHCO₃ (saturated solution, 2 mL) at rt. Thereaction mixture was stirred at rt for 3 h. The mixture was concentratedin vacuo and the residue was purified by column to give the desiredcompound (4.96 g, yield, 73%) as a yellow oil. LC-MS (ESI⁺): m/z 382.43(M+H)⁺.

Step 2—2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl4-methylbenzenesulfonate

To a stirred solution of tert-butyl(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)carbamate (2.0 g, 5.25 mmol)in DCM (10 mL) was added TEA (1.06 g, 10.5 mmol) at rt. To the abovereaction mixture was added dropwise TsCl (2.0 g, 10.5 mmol) in DCM (5mL) at 0° C. After the addition, the reaction was stirred at rtovernight. The mixture was concentrated in vacuo and the residue waspurified via column chromatography (Petroleum ether/EtOAc=5%-80%) togive the desired compound (1.85 g, 66%) as a yellow oil. LC-MS (ESI⁺):m/z 536.50 (M+H)⁺.

N-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-amine(Intermediate OP)

Step 1—Tert-Butyl4-(trans-4-(((benzyloxy)carbonyl)amino)cyclohexyl)piperazine-1-carboxylate(3)

The reaction was performed in parallel for two batches: to a solution oftert-butyl piperazine-1-carboxylate (24.0 g, 129 mmol) in DCM (400 mL)was added benzyl N-(4-oxocyclohexyl)carbamate (31.9 g, 129 mmol, CAS#16801-63-1), HOAc (3.15 g, 52.5 mmol) and NaBH(OAc)₃ (81.9 g, 387 mmol)successively at 0-10° C., and the mixture was stirred at 15° C. for 16hours under N₂. On completion, the mixture of two batches was combined,basified to pH=8 with sat.aq.NaHCO₃, and partitioned. The aqueous phasewas extracted with DCM (2×200 mL). The combined organic layer was washedwith brine (300 mL), dried over Na₂SO₄, filtered and concentrated invacuum. The residue was purified by prep-HPLC (column: Phenomenex GeminiC18 250*50 mm*10 um; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 50%-75%, 26 MIN, 40% min) to give two fractions. Thefirst fraction is the title compound (20.0 g, 18% yield) as white solid.¹H NMR (400 MHz, CDCl₃) b ppm 7.46-7.29 (m, 5H), 5.09 (s, 2H), 4.57 (s,1H), 3.43 (m, 5H), 2.50 (m, 4H), 2.28 (m, 1H), 2.10 (d, J=12.0 Hz, 2H),1.90 (d, J=11.6 Hz, 2H), 1.46 (s, 9H), 1.40-1.27 (m, 2H), 1.22-1.08 (m,2H). The second fraction is undesired cis-isomer (12.7 g, 110% yield).

Step 2—Tert-Butyl 4-(trans-4-aminocyclohexyl)piperazine-1-carboxylate(4)

A mixture of tert-butyl4-[4-(benzyloxycarbonylamino)cyclohexyl]piperazine-1-carboxylate (8.00g, 16.4 mmol) and Pd/C (800 mg, 10% purity) in MeOH (80 mL) was stirredat 25° C. for 2 hours under H₂ (15 Psi). On completion, the mixture wasfiltered, and the cake was washed with MeOH (50 mL). The filtrate andwashings were combined and concentrated in vacuum to give the titlecompound (5.3 g, crude) as white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm3.49-3.21 (m, 4H), 2.64-2.58 (m, 1H), 2.54 (m, 4H), 2.31-2.20 (m, 1H),1.88 (t, J=15.2 Hz, 4H), 1.45 (s, 9H), 1.34-1.22 (m, 2H), 1.17-1.05 (m,2H).

Step 3—Tert-Butyl4-[4-[(5-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazine-1-carboxylate(6)

5-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (250 mg, 1.08 mmol, CAS#1403767-33-8), DIPEA (555 mg, 4.30 mmol) and tert-butyl4-(4-aminocyclohexyl)piperazine-1-carboxylate (350 mg, 1.23 mmol) weresuspended in IPA (5 mL) under nitrogen and sealed into a microwave tube.The resulting suspension was heated to 150° C. for 3 hours undermicrowave irradiation. On completed, the mixture was concentrated invacuo. The crude product was triturated with methanol (5 mL) to give thetitle compound (300 mg, 58% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.92 (s, 1H), 7.72 (d, J=2.8 Hz, 1H), 6.80 (d, J=2.8 Hz, 1H),6.61 (d, J=6.8 Hz, 1H), 4.08-4.00 (m, 1H), 3.32-3.20 (m, 4H), 2.93-2.91(m, 1H), 2.45-2.41 (m, 2H), 2.11-2.07 (m, 2H), 1.84-1.80 (m, 1H),1.57-1.16 (m, 16H); LC-MS (ESI⁺) m/z 481.2 & 479.2 (M+H)⁺.

Step 4—Tert-Butyl4-[4-[[5-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]cyclohexyl]piperazine-1-carboxylate(8)

A mixture of tert-butyl4-[4-[(5-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazine-1-carboxylate(300 mg, 625 umol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(394 mg, 1.88 mmol, CAS #287944-16-5), Brettphos-Pd-G₃ (56.7 mg, 62.5umol) and K₂CO₃ (173 mg, 1.25 mmol) in a mixed solvent of THF (20 mL)and H₂O (4 mL) was degassed and purged with N₂ for 3 times, and then themixture was stirred at 55° C. for 12 hrs under N₂ atmosphere. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas washed with water (60 mL), extracted with ethyl acetate (3×50 mL).The organic layer was dried with Na₂SO₄, filtrated and concentrated invacuo. The crude product was purified by reversed-phase HPLC (0.1% FAcondition) to give the title compound (220 mg, 73% yield) as yellow oil.¹H NMR (400 MHz, DMSO-d₆) δ 7.89 (s, 1H), 7.62 (d, J=2.8 Hz, 1), 6.66(d, J=2.8 Hz, 1H), 6.20 (d, J=8.0 Hz, 1H), 5.82 (s, 1H), 4.22-4.19 (m,2H), 3.98-3.94 (m, 1H), 3.84 (t, J=5.2 Hz, 2H), 3.28-3.26 (m, 4H),2.46-2.44 (m, 4H), 2.36 (t, J=10.8 Hz, 1H), 2.10-2.07 (m, 2H), 1.83-1.80(m, 2H), 1.39 (s, 9H), 1.37-1.23 (m, 4H); LC-MS (ESI⁺) m/z 483.4 (M+H)⁺.

Step 5—Tert-Butyl4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazine-1-carboxylate(9)

To a solution of tert-butyl4-[4-[[5-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]amino]cyclohexyl]piperazine-1-carboxylate (220 mg, 455 umol) in methanol(30 mL) was added Pd/C (100 mg, 10%, wt) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 16 hours. On completion, thereaction mixture was filtered. The filtrate was concentrated in vacuo togive the title compound (190 mg, 86% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 7.78 (s, 1H), 7.54 (d, J=2.8 Hz, 1H), 6.53 (d,J=2.8 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H), 4.17-3.97 (m, 1H), 3.92-3.88 (m,2H), 3.57-3.51 (m, 2H), 3.44-3.38 (m, 1H), 3.29-3.27 (m, 4H), 2.45-2.43(m, 4H), 2.35-2.29 (m, 1H), 2.01-1.98 (m, 2H), 1.84-1.81 (m, 2H),1.79-1.72 (m, 2H), 1.66-1.63 (m, 2H), 1.57-1.47 (m, 2H), 1.39 (s, 9H),1.37-1.28 (m, 2H); LC-MS (ESI⁺) m/z 485.4 (M+H)⁺.

Step6—N-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-amine(Intermediate OP)

To a solution of tert-butyl4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazine-1-carboxylate (180 mg, 345 umol) in DCM (3 mL) wasadded HCl/dioxane (4 M, 50 mL). The reaction mixture was stirred at 20°C. for 20 minutes. On completion, the mixture was filtered andconcentrated in vacuo to give the title compound (145 mg, 99% yield) asa white solid. LC-MS (ESI⁺) m/z 385.3 (M+H)⁺.

Step7—1-[4-[4-[(5-Tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethanone(10)

To a solution ofN-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-amine(153 mg, 363 umol, HCl salt) and AcOH (24.0 mg, 399 umol) in DMF (3 mL)was added HATU (165 mg, 436 umol). Then, DIPEA (187 mg, 1.45 mmol) wasadded. The reaction mixture was stirred at 20° C. for 0.5 hr. Oncompletion, the reaction mixture was concentrated in vacuo. The crudeproduct was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 3%-33%, 10min) to give the title compound (94.0 mg, 61% yield) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 7.79 (s, 1H), 7.54 (d, J=2.8 Hz, 1H), 6.54 (d,J=2.8 Hz, 1H), 6.20 (d, J=8.0 Hz, 1H), 4.14-4.01 (m, 1H), 3.91 (dd,J=3.2, 10.8 Hz, 2H), 3.55 (t, J=10.8 Hz, 2H), 3.44-3.40 (m, 6H),2.58-2.54 (m, 2H), 2.43-2.39 (m, 1H), 2.04-2.00 (m, 2H), 1.98 (s, 3H),1.87-1.85 (m, 2H), 1.78-1.72 (m, 2H), 1.71-1.59 (m, 2H), 1.58-1.47 (m,2H), 1.44-1.31 (m, 2H); LC-MS (ESI⁺) m/z 427.3 (M+H)⁺.

N1-methyl-N4-(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine(Intermediate OO)

Step 1—Tert-Butyl N-[4-(dibenzylamino)cyclohexyl]carbamate (2)

To a solution of tert-butyl N-(4-aminocyclohexyl)carbamate (3.00 g, 14.0mmol, CAS #177906-48-8) in ACN (50 mL) was added K₂CO₃ (5.80 g, 42.0mmol) and BnBr (7.18 g, 42.0 mmol). The mixture was stirred at 60° C.for 16 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography to give the title compound (4.60 g, 83% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.38-7.26 (m, 8H), 7.24-7.14(m, 2H), 6.58 (d, J=8.0 Hz, 1H), 3.56 (s, 4H), 3.16 (d, J=8.4 Hz, 1H),2.32 (t, J=12.0 Hz, 1H), 1.78 (d, J=10.4 Hz, 4H), 1.49-1.38 (m, 2H),1.35 (s, 9H), 1.08-0.91 (m, 2H); LC-MS (ESI⁺) m/z 395.3 (M+H)⁺.

Step 2—Tert-Butyl N-[4-(dibenzylamino)cyclohexyl]-N-methyl-carbamate (3)

To a solution of tert-butyl N-[4-(dibenzylamino)cyclohexyl]carbamate(4.00 g, 10.1 mmol) in DMF (80 mL) was added NaH (810 mg, 20.2 mmol, 60%purity) at 0° C. The mixture was stirred at 0° C. for 0.5 hour, and thenMeI (2.88 g, 20.2 mmol) was added. The mixture was stirred at 20° C. for16 hours. On completion, the reaction mixture was quenched by water (60mL) at 0° C., and then extracted with EA (3×100 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was triturated with DMF (8 mL) togive the title compound (3.70 g, 89% yield) as white solid. ¹H NMR (400MHz, CDCl₃) δ 7.38 (d, J=7.2 Hz, 4H), 7.30 (t, J=7.2 Hz, 4H), 7.25-7.18(m, 2H), 3.63 (s, 4H), 2.66 (s, 3H), 2.52-2.39 (m, 1H), 1.96 (d, J=11.6Hz, 2H), 1.72 (d, J=11.2 Hz, 2H), 1.58-1.30 (m, 14H); LC-MS (ESI⁺) m/z409.2 (M+H)⁺.

Step 3—Tert-Butyl N-(4-aminocyclohexyl)-N-methyl-carbamate (4)

To a solution of tert-butylN-[4-(dibenzylamino)cyclohexyl]-N-methyl-carbamate (2.60 g, 6.36 mmol)in a mixed solvent of MeOH (10 mL) and EA (50 mL) was added Pd(OH)₂/C(200 mg, 10% purity), Pd/C (200 mg, 10% purity) and NH3H2O (182 mg, 0.2mL, 38% purity) under N₂ atmosphere. The suspension was degassed undervacuum and purged with H₂ three times. The mixture was stirred at 20° C.for 16 hours under H₂ (15 psi). On completion, the reaction mixture wasfiltered and concentrated in vacuo to give the title compound (1.40 g,96% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.70 (s, 3H),2.64-2.57 (m, 1H), 1.91 (d, J=12.0 Hz, 2H), 1.67 (d, J=12.0 Hz, 2H),1.58-1.48 (m, 2H), 1.45 (s, 9H), 1.32-1.17 (m, 3H).

Step 4—Tert-ButylN-[4-[[5-bromo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]-N-methyl-carbamate(6)

To a solution of tert-butyl N-(4-aminocyclohexyl)-N-methyl-carbamate(1.25 g, 5.47 mmol) and2-[(5-bromo-4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(2.18 g, 6.02 mmol, from I-442) in ACN (50 mL) was added Na₂CO₃ (1.16 g,10.9 mmol). The mixture was stirred at 85° C. for 16 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give a residue. The residue was purified by silica gel chromatographyto give the title compound (2.40 g, 79% yield) as light yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.55 (s, 1H), 6.06 (d, J=8.0 Hz,1H), 5.46 (s, 2H), 4.06 (s, 1H), 3.49 (t, J=8.0 Hz, 2H), 3.32-3.29 (m,1H), 2.69 (s, 3H), 2.08 (d, J=10.0 Hz, 2H), 1.73-1.54 (m, 4H), 1.54-1.44(m, 2H), 1.40 (s, 9H), 0.81 (t, J=8.0 Hz, 2H), −0.09 (s, 9H); LC-MS(ESI⁺) m/z 554.2 (M+H)⁺.

Step 5—Tert-ButylN-[4-[[5-(3,6-dihydro-2H-pyran-4-yl)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]-N-methyl-carbamate

To a mixture of tert-butylN-[4-[[5-bromo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]-N-methyl-carbamate(1.20 g, 2.16 mmol) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.36 g, 6.49 mmol, CAS #287944-16-5) in a mixed solvent of THF (20 mL)and H₂O (4 mL) was added BrettPhos-Pd-G₃ (196 mg, 216 umol) and K₂CO₃(598mg, 4.33 mmol). The mixture was degassed and purged with N₂ for 3times, and then the mixture was stirred at 55° C. for 16 hours under N₂atmosphere. On completion, the reaction mixture was filtered andconcentrated in vacuo to give a residue. The residue was washed withwater (30 mL) and extracted with EA (6×30 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by silica gel chromatography togive the title compound (0.92 g, 76% yield) as light yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.20 (s, 1H), 7.36 (s, 1H), 5.81 (s, 1H), 5.62(d, J=8.0 Hz, 1H), 5.47 (s, 2H), 4.24 (d, J=2.4 Hz, 2H), 4.07-3.94 (m,1H), 3.84 (t, J=5.6 Hz, 2H), 3.49 (t, J=8.0 Hz, 2H), 2.69 (s, 3H), 2.44(s, 2H), 2.09 (d, J=10.4 Hz, 2H), 1.73-1.55 (m, 4H), 1.45-1.35 (m, 11H),0.81 (t, J=8.0 Hz, 2H), −0.08 (s, 9H); LC-MS (ESI⁺) m/z 558.4 (M+H)⁺.

Step 6—Tert-ButylN-methyl-N-[4-[[5-tetrahydropyran-4-yl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate (9)

To a solution of tert-butylN-[4-[[5-(3,6-dihydro-2H-pyran-4-yl)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]-N-methyl-carbamate (200mg, 358 umol) in MeOH (10 mL) was added Pd/C (60.0 mg, 10% purity) underN₂. The suspension was degassed in vacuo and purged with H₂ three times.The mixture was stirred under H₂ (15 psi) at 25° C. for 16 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (195 mg, 88% yield) as light yellow solid.LC-MS (ESI⁺) m/z 560.3 (M+H)⁺.

Step7—[4-[[4-(Methylamino)cyclohexyl]amino]-5-tetrahydropyran-4-yl-pyrrolo[2,3-d]pyrimidin-7-yl]methanol(10)

To a solution of tert-butylN-methyl-N-[4-[[5-tetrahydropyran-4-yl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate (190 mg, 339umol) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL). The reactionmixture was stirred at 45° C. for 16 hours. On completion, the reactionmixture was concentrated in vacuo to give the title compound (120 mg,63% yield) as light yellow solid. LC-MS (ESI⁺) m/z 360.1 (M+H)⁺.

Step8—N1-methyl-N4-(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine(Intermediate OQ)

To a solution of[4-[[4-(methylamino)cyclohexyl]amino]-5-tetrahydropyran-4-yl-pyrrolo[2,3-d]pyrimidin-7-yl]methanol (120 mg, 303 umol) in a mixed solvent of THF (6mL) and H₂O (1.5 mL) was added LiOH H₂O (50.8 mg, 1.21 mmol). Themixture was stirred at 25° C. for 16 hours. On completion, the reactionmixture was acidified with 1N HCl solution till pH=7, and thenconcentrated in vacuo give a residue. The residue was purified byprep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobile phase:[water (0.04% NH₃H₂O+10 mM NH₄HCO₃) to give the title compound (12.1 mg,12% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s, 1H),8.07 (s, 1H), 6.83 (s, 1H), 5.53 (d, J=8.0 Hz, 1H), 4.13-3.99 (m, 1H),3.90 (dd, J=3.2, 11.2 Hz, 2H), 3.54 (t, J=11.6 Hz, 2H), 3.28-3.19 (m,2H), 2.32-2.21 (m, 4H), 2.01-1.80 (m, 6H), 1.60-1.49 (m, 2H), 1.47-1.32(m, 2H), 1.20-1.01 (m, 2H); LC-MS (ESI⁺) m/z 330.3 (M+H)⁺.

3-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanal (Intermediate OR)

Step1—(E)-3-(4-(3-hydroxyprop-1-en-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00g, 2.96 mmol, Intermediate HP), prop-2-en-1-ol (0.500 g, 8.61 mmol),DIPEA (764. mg, 5.91 mmol), Pd₂(dba)₃ (271 mg, 296 umol) and P(t-Bu)₃(1.20 g, 591 umol, 10% purity in hexane solution) in dioxane (50 mL) wasde-gassed and then heated to 30° C. for 24 hours under N₂. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by reverse phase chromatography (0.1% FA condition) to givethe title compound (860 mg, 88% yield) as a yellow solid. LC-MS (ESI⁺)m/z 316.1 (M+H)⁺.

Step2—3-(4-(3-Hydroxypropyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-[4-[(E)-3-hydroxyprop-1-enyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(860 mg, 2.73 mmol) in THF (10 mL) was added Pd/C (100 mg, 163 umol)(10%, wt) under N₂. The suspension was degassed under vacuum and purgedwith H₂ several times. The mixture was stirred under H₂ (15 psi) at 20°C. for 48 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was purified by reversed-phasechromatography (0.10% FA condition) to give the title compound (450 mg,44% yield) as a yellow solid. LC-MS (ESI⁺) m/z 318.1 (M+H)⁺.

Step3—3-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propanal

To a solution of3-[4-(3-hydroxypropyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(250 mg, 788 umol) in DCM (10 mL) was added DMP (400 mg, 945 umol). Thereaction mixture was stirred at 25° C. for 12 hours. On completion, thereaction mixture was quenched with saturated sodium thiosulfate (50 mL)and saturated aq.NaHCO₃, then extracted with DCM (3×150 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate, and filtered. The filtrate was concentrated invacuo to give the title compound (240 mg, 96% yield) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 9.80 (s, 1H), 8.33-8.04 (m, 1H), 6.96-6.91 (m,1H), 6.82 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 5.13 (dd, J=5.6,12.4 Hz, 1H), 3.61 (s, 3H), 3.21 (t, J=7.6 Hz, 2H), 2.81 (t, J=7.6 Hz,2H).

3-(4-(3-(((6-(Aminomethyl)hexahydrofuro[3,2-b]furan-3-yl)methyl)amino)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(Intermediate OS)

To a solution of3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propanal(120 mg, 380 umol, Intermediate OR) and[6-(aminomethyl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]methanamine(328 mg, 1.90 mmol, Intermediate OT) in DMF (5 mL) was added 4Å MS (100mg) and HOAc (45.7 mg, 761 umol). The reaction mixture was stirred at80° C. for 1 hour. Then, NaBH₃CN (47.8 mg, 761 umol) was added. Theresulting reaction mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (column: Shim-pack C18 150*25*10 um; mobilephase: [water (0.225% FA)-ACN]; B %: 1%-25%, 10 min) to give the titlecompound (50.0 mg, 23% yield) as a white solid. LC-MS (ESI⁺) m/z 472.3(M+H)⁺.

[6-(Aminomethyl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]methanamine(Intermediate OT)

Step1—[(3R,3aS,6R,6aS)-6-(Trifluoromethylsulfonyloxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]trifluoromethanesulfonate

To a solution of(3R,3aR,6R,6aR)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-diol (25.0g, 171 mmol, CAS #641-74-7) and pyridine (32.4 g, 410 mmol) in DCM (250mL) at 0° C. was added Tf₂0 (115 g, 410 mmol, 67.74 mL) dropwise. Thenthe mixture was stirred at rt for 3 hours. On completion, the reactionmixture was acidified with 1N aq.HCl until the pH=3. The mixture waswashed with H₂O (3×50 mL). The organic layer was basified with saturatedNaHCO₃ solution until the pH=8. The organic layer was then washed withbrine (2×30 mL) and dried over Na₂SO₄, then filtered. The filtrate wasconcentrated in vacuo to give the title compound (70.0 g, 99% yield) asyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 5.28-5.19 (m, 2H), 4.82-4.75 (m,2H), 4.22-4.12 (m, 4H).

Step 2—2,3,3A,5,6,6a-Hexahydrofuro[3,2-b]furan-3,6-dicarbonitrile

To a mixture of 18-crown-6 (58.9 g, 223 mmol) and KCN (48.4 g, 743 mmol)in THF (400 mL) was added a solution of[(3R,3aS,6R,6aS)-6-(trifluoromethylsulfonyloxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]trifluoromethanesulfonate(61.0 g, 148 mmol) in THF (400 mL). Then the reaction mixture wasstirred at 0° C. for 3 hours. On completion, the reaction was warmed toroom temperature, then the mixture was poured into cold water (200 mL)and extracted with chloroform (5×100 mL). The combined organic layerswere dried over Mg₂SO₄, then filtered. The filtrate was decolorized withactivated carbon. After filtration through celite, the filtrate wasconcentrated in vacuo. The residue was purified by Prep-TLC (SiO₂,PE:EA=1:1) to give the title compound (5.00 g, 20% yield) as yellowishsolid. ¹H NMR (400 MHz, CDCl₃) δ 5.03 (s, 2H), 4.14-4.07 (m, 4H),3.22-3.19 (m, 2H).

Step3—[6-(Aminomethyl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]methanamine

To a solution of2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3,6-dicarbonitrile (2.50 g, 15.2mmol) in THF (25.0 mL) was added BH₃-Me₂S (10.0 M, 25.0 mL) dropwise.The mixture was stirred at 20° C. for 16 hours under N₂. On completion,the reaction mixture was quenched with MeOH (50 mL). The mixture wasconcentrated in vacuo to give the title compound (2.62 g, 100% yield) aswhite solid. ¹H NMR (400 MHz, D₂O) δ 4.30-3.86 (m, 1H), 3.71-3.47 (m,4H), 3.12-2.91 (m, 3H), 2.68-2.50 (m, 2H), 1.68-1.40 (m, 2H).

3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propanal(Intermediate OU)

Step1—3-[5-(3-Hydroxyprop-1-enyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00g, 2.96 mmol, Intermediate HN) and prop-2-en-1-ol (350 mg, 6.03 mmol) indioxane (10.0 mL) was added P(t-Bu)₃ (1.20 g, 591 umol, 10 wt %),Pd₂(dba)₃ (270 mg, 295 umol) and DIPEA (496 mg, 3.84 mmol). The mixturewas stirred at 20° C. for 16 hours under N₂. On completion, the mixturewas concentrated in vacuo. The residue was purified by reverse phasechromatography (0.1% FA) to give the title compound (750 mg, 80% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.74 (s, 1H), 11.08 (s,1H), 9.80-9.62 (m, 1H), 7.11-7.07 (m, 1H), 7.01 (d, J=8.0 Hz, 1H),6.95-6.93 (m, 1H), 6.96-6.83 (m, 1H), 5.41-5.25 (m, 1H), 3.31 (s, 3H),2.94-2.89 (m, 2H), 2.81-2.76 (m, 1), 2.75-2.65 (m, 1), 2.65-2.54 (m,1H), 2.04-1.94 (m, 1H).

Step2—3-[5-(3-Hydroxypropyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-[5-[(E)-3-hydroxyprop-1-enyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (750 mg, 2.38 mmol) in THF (30.0 mL) was added PtO₂ (54.0 mg,237 umol). The mixture was stirred at 20° C. for 16 hours under H₂ (15psi). On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by reverse phasechromatography (0.1% FA) to give the title compound (220 mg, 29% yield)as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.06-6.96 (m,2H), 6.90-6.82 (m, 1H), 5.38-5.27 (m, 1H), 3.45-3.42 (m, 2H), 3.33 (s,3H), 2.98-2.78 (m, 2H), 2.76-2.68 (m, 1), 2.64-2.60 (m, 1), 2.59-2.52(m, 1H), 2.05-1.93 (m, 1H), 1.83-1.66 (m, 2H).

Step3—3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propanal

To a solution of3-[5-(3-hydroxypropyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(220 mg, 693 umol) in DCM (10.0 mL) was added DMP (352 mg, 831 umol).The mixture was stirred at 25° C. for 1 hour. On completion, the mixturewas quenched with saturated Na₂S₂O₃ (30 mL) and washed with saturatedNaHCO₃ (2×30 mL). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give the title compound (200 mg,910% yield) as yellow solid. LC-MS (ESI⁺) m/z 316.1 (M+H)⁺.

3-[5-[3-[[3-(Aminomethyl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]methylamino]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate OV)

To a solution of3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propanal(190 mg, 602 umol, Intermediate OU),[6-(aminomethyl)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]methanamine(518 mg, 3.01 mmol, Intermediate OT) in DMF (6.00 mL) was added HOAc(72.3 mg, 1.21 mmol) and 4Å molecular sieves (10.0 mg). The mixture wasstirred at 80° C. for 1 hour. The mixture was cooled to 25° C., thenNaBH₃CN (75.7 mg, 1.21 mmol) was added, and the mixture was stirred at25° C. for 16 hours. On completion, the mixture was quenched with H₂O (1mL), filtered and the filtrate was concentrated in vacuo. The residuewas purified by prep-HPLC (column: Shim-pack C18 150*25*10 um; mobilephase: [water (0.225% FA)-ACN]; B %: %-30%, 10 min) to give the titlecompound (120 mg, 42% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.19 (s, 1H), 8.04 (s, 1H), 7.07-6.98 (m, 2H), 6.87 (d, J=7.2 Hz, 1H),5.42-5.28 (m, 1H), 4.42-4.35 (m, 2H), 4.31-4.22 (m, 2H), 3.85-3.78 (m,2H), 3.33 (s, 3H), 3.12-3.06 (m, 2H), 3.02-2.94 (m, 2H), 2.79-2.73 (m,1H), 2.66-2.64 (m, 1H), 2.47-2.46 (m, 1H), 2.32-2.24 (m, 6H), 2.07-1.94(m, 1H), 1.79-1.70 (m, 2H).

4-Amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carbonitrile (IntermediateOW) (IRW-598)

Step 1—1-[4-(Hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carbonitrile

To a mixture of 4-nitro-1H-pyrazole-3-carbonitrile (3.00 g, 21.7 mmol,CAS #61241-07-4) and [4-(hydroxylmethyl)phenyl] boronic acid (2.20 g,14.4 mmol, CAS #59012-93-2) in mixed solvents of pyridine (25 mL) andDCM (75 mL) was added Cu(OAc)₂ (3.94 g, 21.7 mmol) under O₂ (15 psi),then the mixture was stirred at 20° C. for 12 hours. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (SiO₂) to give the titlecompound (3.00 g, 78% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.90 (s, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H),4.62 (s, 2H), 4.39 (s, 1H).

Step 2—4-Amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carbonitrile

To a mixture of1-[4-(hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carbonitrile (3.00 g,12.3 mmol) in a mixed solvents of EtOH (120 mL) and H₂O (30 mL) wasadded NH₄Cl (6.57 g, 123 mmol). The mixture was heated to 65° C. Then Fe(6.86 g, 123 mmol) was added in portions. The reaction mixture wasstirred at 65° C. for 1 hour. On completion, the reaction mixture wascooled to 25° C., filtered and concentrated in vacuo to give a residue.The residue was purified by column chromatography (SiO₂) to give thetitle compound (1.20 g, 42% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.84 (s, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H),5.25 (t, J=5.6 Hz, 1H), 5.00 (s, 2H), 4.50 (d, J=5.6 Hz, 2H).

Tert-butylN-[4-[4-[[3-cyano-1-(4-formylphenvl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(Intermediate OX)

Step 1—Tert-ButylN-[4-[4-[[3-cyano-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a mixture of4-amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carbonitrile (300 mg, 1.40mmol, Intermediate OW) and2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (503 mg, 1.40 mmol, Intermediate OM) in DMF (10 mL) was added DIPEA(543 mg, 4.20 mmol) and HATU (639 mg, 1.68 mmol). The reaction mixturewas stirred at 20° C. for 1 hour. On completion, the reaction mixturewas concentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (453 mg,52% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.73 (s, 1H),9.08 (s, 1H), 8.85 (s, 1H), 8.61 (d, J=5.2 Hz, 1H), 8.36 (s, 1), 7.86(d, J=8.8 Hz, 2H), 7.72 (d, J=1.2, 4.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 2H),5.34 (t, J=5.6 Hz, 1H), 4.58 (d, J=5.6 Hz, 2H), 3.88 (d, J=6.8 Hz, 2H),1.52 (s, 9H), 1.20-1.15 (m, 1H), 0.46-0.37 (m, 2H), 0.30-0.20 (m, 2H).

Step 2—Tert-ButylN-[4-[4-[[3-cyano-1-(4-formylphenvl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a mixture of tert-butylN-[4-[4-[[3-cyano-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate (350 mg, 630umol) in DCM (15 mL) was added DMP (294 mg, 693 umol). The reaction wasstirred at 20° C. for 1 hour. On completion, a solution of sodiumthiosulfate aqueous solution (20 mL) and saturated sodium bicarbonate(20 mL) was added into the mixture and stirred for 10 minutes. Then themixture was extracted with DCM (2×20 mL). The combined organic layer waswashed with brine (2×30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give title compound (320 mg, 91% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.85 (s, 1H), 10.07 (s, 1H),9.14-9.02 (m, 2H), 8.61 (d, J=5.2 Hz, 1H), 8.36 (s, 1H), 8.23-8.15 (m,2H), 8.14-8.08 (m, 2H), 7.72 (d, J=5.2 Hz, 1), 3.88 (d, J=7.2 Hz, 2H),1.52 (s, 9H), 1.26-1.11 (m, 1H), 0.49-0.37 (m, 2H), 0.30-0.21 (m, 2H).

6-Bromo-3H-1,3-benzoxazol-2-one (Intermediate OY)

To a solution of 2-amino-5-bromo-phenol (4.50 g, 23.9 mmol, CAS#38191-34-3) in THF (120 mL) was added CDI (4.66 g, 28.7 mmol). Thereaction mixture was stirred at 70° C. for 2 hours. On completion, thereaction mixture was added to water (240 mL) and the mixture wasadjusted pH=6˜ 7 with 2.0 M aq.HCl, then ethyl acetate (150 mL) wasadded. The organic layer was separated and washed with a saturatedsodium chloride solution (20 mL), dried over anhydrous sodium sulfate,filtered, and concentrated in vacuo. The residue was recrystallized intoluene (60 mL) to give the title compound (3.75 g, 90% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (d, J=1.6 Hz, 1H),7.32 (dd, J=1.8, 8.4 Hz, 1H), 7.06 (s, 1H), 7.04-7.01 (m, 1H). LC-MS(ESI⁺) m/z 216.0 & 214.0 (M+Na)⁺.

3-(6-Bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (Intermediate

Step1—3-(6-Bromo-2-oxo-1,3-benzoxazol-3-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a solution of 6-bromo-3H-1,3-benzoxazol-2-one (2.00 g, 9.35 mmol,Intermediate OY) in THF (50 mL) was added t-BuOK (1.26 g, 11.2 mmol).The reaction mixture was stirred at 0° C. for 0.5hour. Subsequently,[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (4.81 g, 12.6 mmol, Intermediate IQ) in asolution of THF (30 mL) was added dropwise. The resulting reactionmixture was stirred at 20° C. for 0.5 hour under N₂. On completion, thereaction mixture was quenched with saturated NH₄Cl (100 mL), andextracted with ethyl acetate (100 mL). The combined organic layer waswashed with brine (2×100 mL), dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatography (PE:EA:DCM=5:1:2) to give thetitle compound (3.75 g, 90% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 7.22-7.20 (d, J=8.0 Hz, 1H), 6.89-6.87 (d, J=8.0 Hz, 1H),4.90-4.86 (m, 1H), 4.47-4.36 (m, 2H) 3.81 (s, 3H), 2.67-2.64 (m, 1H),2.59-2.54 (m, 2H), 2.40-2.38 (m, 1H). LC-MS (ESI⁺) m/z 466.9 & 468.9(M+Na)⁺.

Step 2—3-(6-Bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione

To a mixture of3-(6-bromo-2-oxo-1,3-benzoxazol-3-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione(2.00 g, 4.49 mmol) in ACN (60 mL) was added CAN (7.39 g, 13.4 mmol) insolution of H₂O (20 mL), and the reaction mixture was degassed andpurged with N₂ for 3 times. Then the mixture was stirred at 20° C. for 3hours under N₂ atmosphere. On completion, the reaction mixture wasfiltered. The filtered cake was collected and dried in vacuo to give thetitle compound (900 mg, 61% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.24 (s, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.48-7.41 (m, 1), 7.27(d, J=8.4 Hz, 1), 5.39 (dd, J=5.2, 12.8 Hz, 1), 3.00-2.80 (m, 1),2.76-2.60 (m, 2H), 2.18-2.15 (m Hz, 1H). LC-MS (ESI⁺) m/z 325.0 &327.0(M+H)⁺.

2—3-[6-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate PA)

Step 1—Tert-ButylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]ethoxy]ethyl]carbamate

3-(6-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (400 mg, 1.23mmol, Intermediate OZ),tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (898 mg, 3.69 mmol,synthesized via Step 1 of Intermediate CQ), Pd(PPh₃)₂Cl₂ (86.3 mg, 123umol), CuI (23.4 mg, 123 umol), 4Å MS (400 mg, 307 umol) and Cs₂CO₃(2.00 g, 6.15 mmol) in DMF (6 mL) was stirred at 80° C. for 2 hoursunder N₂. On completion, the reaction mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by columnchromatography (ACN) to give an impure product. The impure product wasre-purified by reverse phase (0.1% FA condition) to give the titlecompound (340 mg, 54% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ11.23 (s, 1H), 7.53 (s, 1H), 7.37-7.33 (m, 1H), 7.31-7.27 (m, 1H),6.82-6.75 (m, 1H), 5.40 (dd, J=5.2, 12.8 Hz, 1H), 4.39 (s, 2H),3.65-3.60 (m, 2H), 3.57-3.53 (m, 2H), 3.41-3.38 (m, 2H), 3.07-3.02 (m,2H), 2.93-2.81 (m, 1H), 2.72-2.61 (m, 2H), 2.18-2.16 (m, 1H), 1.37 (s,9H), 1.37-1.36 (m, 1H). LC-MS (ESI⁺) m/z 510.2 (M+Na)⁺.

Step 2—Tert-ButylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate(420 mg, 861 umol) in THF (30 mL) was added Pd/C (0.1 g, 10% wt) andPd(OH)₂/C (0.1 g, 10% wt) under N₂. The suspension was degassed undervacuum and purged with H₂ gas several times. The mixture was stirredunder H₂ (15 psi) at 20° C. for 12 hours. On completion, the reactionmixture was filtered and the filtrate was concentrated in vacuo to givethe title compound (440 mg, 93% yield) as yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 11.25 (s, 1H), 7.32 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.11 (d,J=8.0 Hz, 1H), 6.79 (s, 1H), 5.40 (dd, J=5.2, 12.8 Hz, 1H), 3.57-3.53(m, 4H), 3.46-3.43 (m, 4H), 3.13 (d, J=6.0 Hz, 2H), 3.00-2.89 (m, 1H),3.00-2.89 (m, 1H), 2.80-2.67 (m, 4H), 2.25-2.20 (m, 1H), 1.88-1.83 (m,2H), 1.43-1.42 (m, 9H). LC-MS (ESI⁺) m/z 514.2 (M+Na)⁺.

Step3—2-3-[6-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]ethoxy]ethyl]carbamate (150 mg, 305 umol) in DCM (5 mL) was addedHCl/dioxane (4 M, 7.50 mL). The reaction mixture was stirred at 20° C.for 1 hour. On completion, the reaction mixture was concentrated invacuo to give the title compound (130 mg, 99% yield, HCl salt) as awhite solid. LC-MS (ESI⁺) m/z 392.2 (M+H)⁺.

2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]oxazole-4-carboxamide(Intermediate PB)

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (100 mg, 172umol, Intermediate GF) in DCM (3.00 mL) was added HCl/dioxane (4.00 M,3.00 mL), and the mixture was stirred at 25° C. for 0.5 hr. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (80.0 mg, 96% yield) as yellow solid. LC-MS (ESI⁺) m/z 479.2(M+H)⁺.

Tert-Butyl N-(4-hydroxy-4-methyl-hept-6-enyl)carbamate (Intermediate PC)

Step 1—Tert-Butyl N-(4-oxopentyl)carbamate

To a solution of tert-butyl 2-oxopyrrolidine-1-carboxylate (5.00 g, 26.9mmol) in THF (50.0 mL) was added MeMgBr (3.00 M, 10.8 mL) dropwise at−78° C. under N₂, and the mixture was stirred at −78° C. for 3 hrs. Oncompletion, the mixture was poured into cool water (50 mL) and thenextracted with MTBE (2×50 mL). The organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The mixture waspurified by silica gel column (PE:EA=5:1) to give the title compound(4.45 g, 81% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.67 (s,1H), 3.19-3.02 (m, 2H), 2.51-2.47 (m, 2H), 2.14 (s, 3H), 1.80-1.70 (m,2H), 1.42 (s, 9H).

Step 2—Tert-butyl N-(4-hydroxy-4-methyl-hept-6-enyl)carbamate

To a solution of tert-butyl N-(4-oxopentyl)carbamate (2.00 g, 9.94 mmol)in THF (20.0 mL) was added allyl(bromo)magnesium (1.00 M, 12.9 mL)dropwise at −78° C., and the mixture was stirred at 0° C. for 3 hrsunder N₂. On completion, the mixture was quenched with saturated NH₄Cl(30 mL), then extracted with MTBE (3×30 mL). The organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Themixture was purified by silica gel column (PE:EA=5:1) to give the titlecompound (770 mg, 31% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ6.74 (s, 1H), 5.91-5.74 (m, 1H), 5.03 (s, 1H), 4.99 (d, J=3.6 Hz, 1H),4.15 (s, 1H), 2.91-2.83 (m, 2H), 2.15-2.05 (m, 2H), 1.46-1.39 (m, 2H),1.38 (s, 9H), 1.31-1.24 (m, 2H), 1.00 (s, 3H).

3-[5-(7-Amino-4-hydroxy-4-methyl-heptyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate PD)

Step 1—Tert-butylN—[(E)-7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-hydroxy-4-methyl-hept-6-enyl]carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (200mg, 591 umol, Intermediate HN), tert-butylN-(4-hydroxy-4-methyl-hept-6-enyl)carbamate (287 mg, 1.18 mmol,Intermediate PC) in dioxane (12.0 mL) was added tris-o-tolylphosphane(36.0 mg, 118 umol), Pd(OAc)₂ (13.2 mg, 59.1 umol) and DIPEA (1.53 g,11.8 mmol) under N₂. The mixture was stirred at 120° C. for 16 hrs. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% FA) to give the titlecompound (180 mg, 60% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.10 (s, 1H), 7.27 (s, 1H), 7.04 (s, 2H), 6.76 (s, 1H), 6.45-6.34 (m,1H), 6.33-6.21 (m, 1), 5.40-5.30 (m, 1H), 4.26 (s, 1H), 2.92-2.89 (m,1H), 2.89-2.84 (m, 2H), 2.71-2.67 (m, 1H), 2.64-2.56 (m, 1H), 2.30-2.20(m, 2H), 2.08 (s, 3H), 2.05-1.96 (m, 1H), 1.52-1.41 (m, 2H), 1.36 (s,9H), 1.35-1.31 (m, 2H), 1.07 (s, 3H).

Step 2—Tert-butylN-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-hydroxy-4-methyl-heptyl]carbamate

To a solution of tert-butylN—[(E)-7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-hydroxy-4-methyl-hept-6-enyl]carbamate(160 mg, 319 umol) in THF (8.00 mL) was added Pd(OH)₂/C (50.0 mg, 10%wt) and Pd/C (50 mg, 10% wt), and the mixture was stirred at 25° C. for3 hrs under H₂ gas (15 psi). On completion, the mixture was filtered andthe filtrate was concentrated in vacuo to give the title compound (160mg, 99% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1),7.08 (s, 1H), 7.05 (d, J=8.0 Hz, 1), 6.92 (s, 2H), 6.79 (s, 1H),5.44-5.34 (m, 1H), 4.03 (s, 1H), 3.38 (s, 3H), 3.01-2.95 (m, 1H),2.94-2.87 (m, 2H), 2.80-2.69 (m, 2H), 2.68-2.64 (m, 1H), 2.64-2.60 (m,1H), 2.11-2.01 (m, 1H), 1.69-1.59 (m, 2H), 1.48-1.43 (m, 2H), 1.42 (s,9H), 1.40-1.36 (m, 2H), 1.40-1.35 (m, 2H), 1.05 (s, 3H).

Step3—3-[5-(7-Amino-4-hydroxy-4-methyl-heptyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-4-hydroxy-4-methylheptyl]carbamate(150 mg, 298 umol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 1.00mL) at 0° C., and the mixture was stirred at 0° C. for 3 hrs. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% FA) to give the titlecompound (50.0 mg, 41% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.43 (s, 1H), 7.05-6.98 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 5.40-5.28 (m,1H), 3.33 (s, 3H), 2.96-2.87 (m, 1H), 2.74-2.68 (m, 2H), 2.69-2.63 (m,2H), 2.62-2.56 (m, 2H), 2.06-1.98 (m, 1H), 1.67-1.46 (m, 4H), 1.40-1.28(m, 4H), 1.02 (s, 3H).

Benzyl((S)-1-(((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(Intermediate PE)

To a solution of(S)-2-((S)-2-amino-3,3-dimethylbutanoyl)-7-hydroxy-N—((R)-1,2,3,4-tetrahydronaphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide(13.45 g, 30.92 mmol, synthesized via Steps 1-7 of Intermediate MH),(S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanoic acid (7.70 g, 32.47mmol, CAS #21691-41-8) in DMF (150 mL) was added HOBT (4.59 g, 34.01mmoL), EDCI (6.53 g, 34.01 mmoL), and DIPEA (9.97 g, 77.30 mmoL) at rt.The reaction mixture was stirred at r.t. for 4 h. The mixture was thenconcentrated under reduce pressure. Then the mixture was poured into H₂O(200 mL), extracted with EA (3×100 mL), and the combined organic layerswere dried over anhydrous Na₂SO₄. The solid was filtered and thefiltrate was concentrated under reduced pressure. The crude product waspurified by silica gel chromatography eluted with DCM/MEOH=10:1 to givethe title compound (13.7 g, 63% yield) as a white solid. LC/MS (ESI,m/z): [M+1]⁺=655.4.

BenzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(Intermediate PF)

Step 1—Benzyl((S)-1-(((S)-1-((S)-7-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.50 g, 2.29 mmol, Intermediate PE) in CH₃CN (20 mL) was added2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl4-methylbenzenesulfonate (1.23 g, 2.75 mmoL, Intermediate LD), and K₂CO₃(475 mg, 3.44 mmoL). The mixture was stirred at 82° C. overnight. Thereaction mixture was then concentrated under reduced pressure andpurified by silica gel chromatography eluted with DCM/EA=1:1 to give thetitle compound (1.64 g, 77% yield) as a yellow oil. LC/MS (ESI, m/z):[M+1]⁺=931.4.

Step 2—Benzyl((S)-1-(((S)-1-((S)-7-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

A solution of benzyl((S)-1-(((S)-1-((S)-7-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.37 g, 1.47 mmoL) in TFA/DCM=10 mL/5 mL was stirred at rt for 1 h. Themixture was then concentrated under reduced pressure to give the titlecompound (900 mg, 74% yield) as a white solid. LC/MS (ESI, m/z):[M+1]⁺=830.7. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (dd, J=49.6, 8.8 Hz, 1H),7.81-7.56 (m, 4H), 7.35 (s, 5H), 7.16-6.71 (m, 7H), 5.29-4.58 (m, 8H),4.06 (d, J=3.2 Hz, 2H), 3.76-3.73 (m, 2H), 3.64-3.52 (m, 10H), 3.05-2.91(m, 3H), 2.87-2.80 (m, 2H), 2.78-2.61 (m, 3H), 1.91-1.50 (m, 4H), 1.20(d, J=7.2 Hz, 2H), 1.12 (d, J=7.2 Hz, 1H), 0.99 (s, 6H), 0.92 (s, 3H).

Tert-ButylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-(5-oxopentyl)carbamate(Intermediate PG)

Step 1—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[(5-hydroxypentylamino)methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]

A solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (700 mg, 1.21mmol, Intermediate GF) and 5-aminopentan-1-ol (187 mg, 1.81 mmol, CAS#2508-29-4) in DMF (4 mL) and dioxane (20 mL) was stirred at 100° C. for30 min. Then the reaction mixture was cooled to 25° C., and AcOH (217mg, 3.63 mmol, 207 uL) and NaBH(OAc)₃ (769 mg, 3.63 mmol) were added.The reaction mixture was stirred at 25° C. for 1 hour. Then anotherbatch NaBH(OAc)₃ (256 mg, 1.21 mmol) was added to the reaction mixture.The reaction mixture was stirred at 25° C. for another 2 hours. Oncompletion, the reaction was quenched with sat.NaHCO₃ (50 mL) andextracted with EA (2×300 mL). The organic layers were washed with brine(2×70 mL), dried with anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to give the title compound (500 mg, 62% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1), 9.06 (s, 1),8.82 (s, 1), 8.60 (d, J=4.8 Hz, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 7.85(d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 7.44-7.15 (m, 1H), 3.91-3.78(m, 4H), 3.38 (t, J=6.4 Hz, 2H), 2.63 (t, J=6.4 Hz, 2H), 1.54-1.28 (m,13H), 1.25-1.13 (m, 1H), 0.48-0.39 (m, 2H), 0.27-0.20 (m, 2H).

Step 2—Tert-butylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-(5-hydroxypentyl)carbamate

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[(5-hydroxypentylamino)methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(450 mg, 675 umol) in DCM (5 mL) was added (Boc)₂O (147 mg, 675 umol)and TEA (136 mg, 1.35 mmol). The reaction mixture was stirred at 25° C.for 0.5 hour. On completion, the reaction mixture was poured intosat.NaHCO₃ (60 mL) and extracted with EA (2×150 mL). The combinedorganic layers were washed with brine (70 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bysilica column chromatography (PE/EA, 4/1 to 1/1) to give the titlecompound (370 mg, 483 umol, 71% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.05 (s, 1H), 8.80 (s, 1H), 8.60 (d,J=5.2 Hz, 1), 8.32 (s, 1), 7.84 (d, J=8.4 Hz, 2H), 7.70 (dd, J=1.2, 5.2Hz, 1), 7.45-7.11 (m, 2H), 4.42 (s, 2H), 3.87 (d, J=6.8 Hz, 2H), 3.33(s, 9H), 2.59-2.52 (m, 3H), 1.52 (s, 9H), 1.48-1.40 (m, 8H), 1.27-1.23(m, 1H), 0.49-0.32 (m, 2H), 0.32-0.16 (m, 2H).

Step 3—Tert-ButylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-(5-oxopentyl)carbamate

To a solution of tert-butylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-(5-hydroxypentyl)carbamate(370 mg, 483 umol) in DCM (20 mL) was added DMP (225 mg, 531 umol). Thereaction mixture was stirred at 25° C. for 2 hours. On completion, thereaction mixture was quenched sat.Na₂S₂O₃ (10 mL) and extracted with EA(2×100). The combined organic layers were washed with brine (70 mL),dried with anhydrous Na₂SO₄ and filtered. The filtrate was concentratedin vacuo to give the title compound (350 mg, 458 umol, 94% yield) as alight yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.08-8.99(m, 1H), 8.83-8.74 (m, 1H), 8.65-8.52 (m, 1), 8.36-8.27 (m, 1),8.02-7.93 (m, 1), 7.87-7.77 (m, 2H), 7.73-7.69 (m, 1), 7.50-7.44 (m,1H), 7.42-7.37 (m, 1H), 7.30-7.20 (m, 1H), 4.42 (s, 2H), 3.91-3.82 (m,2H), 3.33 (s, 9H), 2.56-2.52 (m, 2H), 2.47-2.34 (m, 1H), 1.55-1.41 (m,15H), 0.92-0.70 (m, 1H), 0.45-0.36 (m, 2H), 0.30-0.18 (m, 2H).

3-[5-(Aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate PH)

Step1—1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbonitrile

To a mixture of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (3.00g, 8.87 mmol, Intermediate HN) in DMF (30 mL) was added Zn(CN)₂ (1.04 g,8.87 mmol) and Pd(PPh₃)₄ (1.03 g, 887 umol). The reaction mixture wasstirred at 100° C. for 3 hours under N₂. On completion, the reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was diluted with water (50 mL) and extracted with EA (3×100 mL).The combined organic layers were dried over Na₂SO₄, filtered and thefiltrate concentrated in vacuo. The residue was purified by prep-HPLC(0.1% FA condition) to give the title compound (1.50 g, 59% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.31-11.00 (m, 1H), 11.15 (s,1H), 7.75 (d, J=1.2 Hz, 1H), 7.57-7.52 (m, 1H), 7.34 (d, J=8.4 Hz, 1H),5.49-5.42 (m, 1H), 3.38 (s, 3H), 2.95-2.83 (m, 1H), 2.79-2.59 (m, 2H),2.10-2.01 (m, 1H).

Step2—3-[5-(Aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbonitrile(1.40 g, 4.92 mmol) in THF (150 mL) was added Raney-Ni (421 mg, 4.92mmol) and HCl/dioxane (4 M, 4.92 mL). The reaction mixture was stirredat 25° C. for 36 hours under H₂ (50 Psi). On completion, the reactionmixture was filtered. The filter cake was washed with DMF (3×10 mL). Thecombined organic layers were concentrated in vacuo to give the titlecompound (1.40 g, 98% yield) as a green solid. LC-MS (ESI⁺) m/z 289.0(M+H)⁺.

2-[2-[Tert-butoxycarbonyl-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]amino]ethoxy]ethylmethanesulfonate (Intermediate PI)

Step1—Tert-buty-(cyclopropymethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-(2-hydroxyethoxy)ethylamino]methyl]phenyl]pyrazol-4-yl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (600 mg, 1.04mmol, Intermediate GF) in a mixed solvent of DMF (10 mL) and THF (100mL) was added 2-(2-aminoethoxy)ethanol (141 mg, 1.35 mmol, CAS#929-06-6) and HOAc (124 mg, 2.07 mmol). The reaction mixture wasstirred at 25° C. for 0.5 hr. Then, NaBH(OAc)₃ (659 mg, 3.11 mmol) wasadded. The resulting reaction mixture was stirred at 25° C. for 16hours. On completion, the reaction mixture was quenched with water (1mL) and concentrated in vacuo. The residue was purified byreversed-phase flash chromatography (FA, 0.1%) to give the titlecompound (400 mg, 57% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.06 (s, 1), 9.05 (s, 1H), 8.82 (s, 1H), 8.60 (d, J=5.2 Hz,1H), 8.32 (s, 1H), 7.86 (d, J=8.8 Hz, 2H), 7.70 (dd, J=1.6, 5.2 Hz, 1H),7.55 (d, J=8.8 Hz, 2H), 7.43-7.15 (m, 1H), 5.75 (s, 1H), 3.92 (s, 2H),3.87 (d, J=6.8 Hz, 2H), 3.56 (t, J=5.6 Hz, 2H), 3.53-3.50 (m, 2H),3.45-3.42 (m, 2H), 2.81 (t, J=5.6 Hz, 2H), 1.52 (s, 9H), 1.24-1.12 (t,J=7.8 Hz, 1H), 0.45-0.38 (m, 2H), 0.27-0.22 (m, 2H).

Step 2—Tert-butylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-[2-(2-hydroxyethoxy)ethyl]carbamate

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-(2-hydroxyethoxy)ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(400 mg, 599 umol) in DCM (20 mL) was added TEA (181 mg, 1.80 mmol) andBoc₂O (156 mg, 718 umol). The reaction mixture was stirred at 25° C. for0.5 hour. On completion, the reaction mixture was poured into sat.NaHCO₃ (30 mL) and extracted with EA (3×100 mL). The combined organiclayers were washed with brine (100 mL), dried over anhydrous Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to give the titlecompound (450 mg, 100% yield) as a white solid. LC-MS (ESI⁺) m/z 768.1(M+H)⁺.

Step3—2-[2-[Tert-butoxycarbonyl-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]amino]ethoxy]ethylmethanesulfonate

To a solution of tert-butylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-[2-(2-hydroxyethoxy)ethyl]carbamate(400 mg, 520 umol) in DCM (20 mL) was added TEA (158 mg, 1.56 mmol). Thereaction mixture was cooled to 0° C. Then, MsCl (119 mg, 1.04 mmol) wasdropwise into the mixture slowly. The reaction mixture was stirred at25° C. for 1 hour. On completion, the reaction mixture was poured intosat.NaHCO₃ (30 mL) and extracted with EA (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried with anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to give the titlecompound (400 mg, 100% yield) as a yellow solid. LC-MS (ESI⁺) m/z 846.2(M+H)⁺.

BenzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(Intermediate PJ)

Step 1—Benzyl((S)-1-(((S)-1-((S)-7-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.0 g, 1.53 mmol, Intermediate PE) in CH₃CN (50 mL) was added2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl4-methylbenzenesulfonate (901 mg, 1.84 mmol, Intermediate ON) and K₂CO₃(317 mg, 2.3 mmol) at rt. The reaction mixture was then stirred at 80°C. for 12 h. The reaction mixture was cooled to rt and filtered. Thefiltrate was concentrated under reduced pressure. The residue waspurified via column chromatography (EtOAc/petroleum ether) to give thetitle compound (1.08 g, 73% yield) as a pale yellow oil. LC/MS (ESI,m/z): [M+1]⁺=974.68.

Step 2—benzyl (()-1-(((S)-1-((S)-7-((14-amino-3,6,9,12-tetraoxatetradecyl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate2,2,2-trifluoroacetate

To a solution of benzyl((S)-1-(((S)-1-((S)-7-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.4 g, 1.43 mmol) in DCM (20 mL) was added TFA (20 mL) and the reactionmixture was stirred at rt for 3 h. The reaction mixture was concentratedunder reduced pressure and the residue was purified via reverse phasecolumn chromatography (ACN/H₂O) to give the title compound (1.341 g,94.8% yield) as as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ: 8.30-8.15(m, 1H), 7.77-7.56 (m, 4H), 7.40-7.35 (m, 5H), 7.18-6.70 (m, 7H),5.28-4.23 (m, 9H), 4.13-4.00 (m, 2H), 3.74 (t, J=4.5 Hz, 2H), 3.69-3.23(m, 14H), 3.02-2.64 (m, 8H), 1.95-1.45 (m, 4H), 1.21-1.11 (m, J3H),0.99-0.91 (m, 9H). LC/MS (ESI, m/z): [M+1]⁺=874.55.

3-(Tert-butoxycarbonylamino)propyl (4-nitrophenyl) Carbonate(Intermediate PK)

To a solution of tert-butyl N-(3-hydroxypropyl)carbamate (0.600 g, 3.42mmol, CAS #58885-58-8) and (4-nitrophenyl) carbonochloridate (759 mg,3.77 mmol, CAS #7693-46-1) in DCM (25 mL) was added TEA (866 mg, 8.56mmol) at 0° C. The reaction mixture was stirred at this temperature for1 hr. On completion, the mixture was quenched with water (10 mL), thenconcentrated in vacuo. The residue was purified by silica gelchromatography (SiO₂) to give the title compound (520 mg, 45% yield) ascolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 8.34-8.25 (m, 2H), 7.44-7.35(m, 2H), 4.77 (s, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.29 (q, J=6.4 Hz, 2H),2.03-1.90 (m, 2H), 1.45 (s, 9H).

3-AminopropylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]carbamate(Intermediate PL)

Step 1—3-(Tert-butoxycarbonylamino)propylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]carbamate

To a solution of3-[5-(aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(120 mg, 416 umol, Intermediate PH) and3-(tert-butoxycarbonylamino)propyl (4-nitrophenyl) carbonate (170 mg,500 umol, Intermediate PK) in DMF (2 mL) was added TEA (84.2 mg, 832umol). The reaction mixture was stirred at 25° C. for 3 hrs. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(110 mg, 54% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.05(s, 1H), 7.64 (s, 1H), 7.10-7.01 (m, 2H), 6.98-6.91 (m, 1), 6.86-6.78(m, 1), 5.43-5.29 (m, 1), 4.19 (d, J=6.0 Hz, 2H), 3.95 (t, J=6.4 Hz,2H), 3.30 (s, 3H), 3.02-2.94 (m, 2H), 2.94-2.84 (m, 1H), 2.69-2.56 (m,2H), 2.09-1.94 (m, 1H), 1.73-1.58 (m, 2H), 1.37 (s, 9H); LC-MS (ESI⁺)m/z 512.3 (M+Na)⁺.

Step 2—3-AminopropylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]carbamate

To a solution of 3-(tert-butoxycarbonylamino)propylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]carbamate(140 mg, 286 umol) in DCM (5 mL) was added TFA (5 mL). The reactionmixture was stirred at 25° C. for 1 hr. On completion, the mixture wasconcentrated in vacuo to give the title compound (140 mg, 97% yield,TFA) as a white solid. LC-MS (ESI⁺) m/z 390.2 (M+H)+

Tert-Butyl4-(3-methyl-2-oxo-1H-benzimidazol-5-yl)piperazine-1-carboxylate(Intermediate PM)

To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.00 g, 17.6mmol, Intermediate IP), tert-butyl piperazine-1-carboxylate (4.92 g,26.4 mmol, CAS #1433238-38-4) and t-BuOK (4.35 g, 38.8 mmol), was addedRuPhos (822 mg, 1.76 mmol) and[2-(2-aminophenyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-diisopropoxyphenyl) phenyl]phosphane (1.37 g, 1.76mmol) in dioxane (100 mL), and the mixture was stirred at 90° C. for 1hr at N₂. On completion, the residue was diluted with H₂O (50 mL) andextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine (150 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was triturated withPE:EA (10:1, 50 mL), filtered and filtered caked was dried under reducedpressure to give the title compound (3.80 g, 65% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H), 6.83 (d, J=8.4 Hz,1H), 6.78 (d, J=2.20 Hz, 1H), 6.60 (dd, J=8.4, Hz, 1H), 3.43-3.50 (m,4H), 3.24 (s, 3H), 2.98-3.03 (m, 4H), 1.42 (s, 9H), LC-MS (ESI⁺) m/z333.1 (M+H)⁺.

3-(3-Methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione(Intermediate PN)

Step 1—Tert-Butyl4-[1-[1-[(4-methoxyphenyl)methyl]2,6-dioxo-3-piperdyl]-3-methyl-2-oxo-benzimidazol-5-yl]piperzine-1-carboxylate2,6-dioxo-3-piperidyl(IntermediatePN)-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-(3-methyl-2-oxo-1H-benzimidazol-5-yl)piperazine-1-carboxylate (3.80 g,11.4 mmol, Intermediate PM) in THF (100 mL) was added t-BuOK (2.57 g,22.9 mmol); then [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (8.72 g, 22.86 mmol, Intermediate IQ) in THF(20 mL) was added at 0° C. The mixture was stirred at 0° C. for 2 hrs.On completion, the residue was diluted with H₂O (50 mL) and extractedwith EtOAc (3×50 mL). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was triturated with PE:EA (10:1,50 mL), filtered and the filtered cake was dried in vacuo to give thetitle compound (3.00 g, 37% yield, 80% purity) as a blue solid. LC-MS(ESI⁺) m/z 564.3 (M+H)⁺.

Step2—3-(3-Methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl4-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]piperazine-1-carboxylate(2.50 g, 4.44 mmol) in DCM (40 mL) was added TFA (38.5 g, 338 mmol, 25.0mL), and the mixture was stirred at 15° C. for 1 hr. Thenmethanesulfonic acid (33.8 g, 351 mmol, 25 mL) was added and the mixturewas stirred at 15° C. for 25 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by reversed-phase HPLC(0.1% FA condition) to give the title compound (700 mg, 40% yield) as ablue solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.89-11.20 (m, 1H), 6.98 (d,J=8.4 Hz, 1H), 6.89 (d, J=1.6 Hz, 1H), 6.67 (dd, J=8.4, 1.6 Hz, 1H),5.31 (dd, J=12.8, 5.6 Hz, 1H), 3.21 (d, J=3.6 Hz, 4H), 3.15 (s, 4H),2.85-2.95 (m, 1H), 2.63-2.75 (m, 2H), 1.96-2.04 (m, 1H), LC-MS (ESI⁺)m/z 344.1 (M+H)⁺.

Tert-Butyl N-methyl-N-(3-prop-2-ynoxypropyl)carbamate (Intermediate PO)

To a solution of 3-bromoprop-1-yne (1.32 g, 11.1 mmol, CAS #106-96-7)and tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (2.00 g, 10.6mmol, CAS #98642-44-5) in THF (20 mL) was added TBAI (234 mg, 634 umol)and KI (263 mg, 1.59 mmol). Then KOH (698 mg, 10.6 mmol, 85% purity) wasadded into the above mixture. The reaction mixture was stirred at 25° C.for 12 hrs. On completion, the mixture was concentrated in vacuo toremove the solvent, the residue was diluted with water (30 mL), thenextracted with EA (3×40 mL). The organic phase was dried over Na₂SO₄,filtered and the filtrate was concentrated in vacuo. The residue waspurified by silica gel chromatography (SiO₂) to give the title compound(1.15 g, 48% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ4.15-4.11 (m, 2H), 3.57-3.49 (m, 2H), 3.29 (t, J=6.8 Hz, 2H), 2.86 (s,3H), 2.42 (t, J=2.4 Hz, 1H), 1.85-1.76 (m, 2H), 1.46 (s, 9H).

3-[3-Methyl-4-[3-[3-(methylamino)propoxy]propyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate PP)

Step 1—Tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate

3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300mg, 887 umol, Intermediate HP), tert-butylN-methyl-N-(3-prop-2-ynoxypropyl)carbamate (504 mg, 2.22 mmol,Intermediate PO), Pd(PPh₃)₂Cl₂ (125 mg, 177 umol), Cs₂CO₃ (1.45 g, 4.44mmol), CuI (33.8 mg, 177 umol) and 4Å molecular sieves (150 mg) in DMF(8 mL) was heated at 80° C. for 2 hrs under N₂. On completion, themixture was concentrated in vacuo. The residue was purified by reversephase (0.1% FA condition) to give the title compound (200 mg, 40% yield)as a yellow solid. LC-MS (ESI⁺) m/z 507.3 (M+Na)⁺.

Step 2—Tert-ButylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]propyl-N-methyl-carbamate

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate (200 mg, 351 umol) in THF (6 mL)was added Pd/C (0.100 g, 10% wt) and Pd(OH)₂/C (0.100 g, 10% wt). Thereaction mixture was stirred at 25° C. for 10 hrs under H₂ (15 Psi)atmosphere. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (200 mg, 93% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.00-6.92 (m,2H), 6.90-6.84 (m, 1H), 5.44-5.24 (m, 1H), 3.56 (s, 3H), 3.44-3.40 (m,4H), 3.22 (t, J=7.2 Hz, 2H), 2.99-2.92 (m, 2H), 2.76 (s, 3H), 2.74-2.69(m, 1H), 2.65-2.58 (m, 2H), 2.04-1.96 (m, 1H), 1.87-1.79 (m, 2H),1.74-1.65 (m, 2H), 1.38 (s, 9H); LC-MS (ESI⁺) m/z 511.3 (M+Na)⁺.

Step3—3-[3-Methyl-4-[3-[3-(methylamino)propoxy]propyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]propyl]-N-methyl-carbamate (200 mg, 327 umol) in DCM (4 mL) wasadded HCl/dioxane (4 M, 3.20 mL). The reaction mixture was stirred at25° C. for 2 hrs. On completion, the mixture was concentrated in vacuoto give the title compound (160 mg, 100% yield, HCl) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.02-6.92 (m, 2H), 6.90-6.83(m, 1H), 5.44-5.24 (dd, J=5.6, 12.4 Hz, 1H), 3.57 (s, 3H), 3.49-3.43 (m,4H), 3.00-2.91 (m, 4H), 2.74-2.53 (m, 6H), 2.04-1.94 (m, 1H), 1.90-1.81(m, 4H); LC-MS (ESI⁺) m/z 389.2 (M+H)⁺.

Tert-Butyl N-(3-prop-2-ynoxypropyl)carbamate (Intermediate PX)

To a mixture of tert-butyl N-(3-hydroxypropyl)carbamate (10.0 g, 57.1mmol, CAS #58885-58-8), 3-bromoprop-1-yne (8.15 g, 68.5 mmol, CAS#106-96-7) in THF (150 mL) was added TBAI (1.26 g, 3.42 mmol) KOH (3.20g, 57.07 mmol) and KI (1.42 g, 8.56 mmol). The mixture was stirred at20° C. for 12 hours. On completion, the reaction mixture wasconcentrated in vacuo to give residue. The residue was purified bycolumn chromatography to give the title compound (6.80 g, 55% yield) asyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.76 (s, 1H), 4.10-4.05 (m, 2H),3.51 (t, J=6.0 Hz, 2H), 3.16 (q, J=6.0 Hz, 2H), 2.37 (t, J=2.4 Hz, 1H),1.74-1.65 (m, 2H), 1.37 (s, 9H).

3-[7-[3-(3-Aminopropoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate PY)

Step 1—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]propyl]carbamate

To a mixture of3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (3.00 g, 9.23mmol, Intermediate JF) and tert-butyl N-(3-prop-2-ynoxypropyl)carbamate(4.92 g, 23.0 mmol, Intermediate PX) in DMF (30 mL) was added Cs₂CO₃(15.0 g, 46.1 mmol), CuI (175 mg, 922 umol) and Pd(PPh₃)₂Cl₂ (647 mg,922 umol). The reaction mixture was stirred at 80° C. for 2 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was diluted with water (50 mL) and extracted with EA (3×100mL). The combined organic layers was dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (2.70 g,63% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (s,1), 7.32 (dd, J=2.0, 7.2 Hz, 1), 7.27-7.19 (m, 2H), 6.81-6.77 (m, 1H),5.39 (dd, J=5.6, 13.2 Hz, 1H), 4.43 (s, 2H), 3.53 (t, J=6.4 Hz, 2H),3.02-2.97 (m, 2H), 2.92-2.81 (m, 1H), 2.73-2.58 (m, 2H), 2.22-2.13 (m,1H), 1.70-1.64 (m, 2H), 1.36 (s, 9H); LC-MS (ESI⁺) m/z 480.2 (M+Na)⁺.

Step 2—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]propyl]carbamate

To a mixture was tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]propyl]carbamate(2.30 g, 5.03 mmol) in THF (200 mL) was added Pd/C (0.6 g, 10% wt) andPd(OH)₂/C (0.6 g, 10% wt). The reaction mixture was stirred at 25° C.for 12 hours under H₂ (15 Psi) atmosphere. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (2.30 g, 99% yield) as off-white solid. LC-MS (ESI⁺) m/z 484.2(M+Na)⁺.

Step3—3-[7-[3-(3-Aminopropoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]propyl]carbamate (2.30 g, 4.98 mmol) in DCM (10 mL) was addedHCl/dioxane (4 M, 10 mL). The reaction mixture was stirred at 25° C. for1 hour. On completion, the reaction mixture was concentrated in vacuo togive the title compound (1.80 g, 90% yield, HCl salt) as off-whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.20 (s, 1H), 7.86 (s, 2H),7.17-7.09 (m, 2H), 7.04-7.00 (m, 1H), 5.37 (dd, J=5.2, 13.2 Hz, 1H),3.47-3.43 (m, 2H), 3.43-3.41 (m, 2H), 2.90-2.84 (m, 2H), 2.83-2.79 (m,1H), 2.78-2.72 (m, 2H), 2.70-2.61 (m, 2H), 2.20-2.10 (m, 1H), 1.91-1.84(m, 2H), 1.83-1.78 (m, 2H).

3-[6-[3-(3-Aminopropoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate PZ)

Step 1—Tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]prop-2-ynoxy]propyl]carbamate

To a mixture of3-(6-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (1.20 g, 3.69mmol, Intermediate OZ) and tert-butyl N-(3-prop-2-ynoxypropyl)carbamate(1.57 g, 7.38 mmol, Intermediate PX) in DMF (30 mL) was added CuI (210mg, 1.11 mmol), Pd(PPh₃)₂Cl₂ (777 mg, 1.11 mmol), Cs₂CO₃ (6.01 g, 18.5mmol) and 3Å molecular sieves (100 mg, 3.69 mmol) under N₂. The reactionmixture was stirred at 80° C. for 2 hours. On completion, the reactionmixture was cooled to 25° C. Then the mixture was filtered andconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (868 mg,42% yield) as brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1),7.74-7.65 (m, 1), 7.61-7.54 (m, 1), 7.36 (d, J=1.0 Hz, 1), 7.30-7.27 (m,1), 6.79 (d, J=8.4 Hz, 1), 5.07 (d, J=5.6, 13.2 Hz, 1), 4.37 (s, 2H),3.66 (t, J=6.0 Hz, 2H), 3.27 (d, J=6.0 Hz, 2H), 3.05-2.95 (m, 1),2.92-2.80 (m, 1), 2.79-2.65 (m, 1), 2.40-2.26 (m, 1), 1.85-1.80 (m, 2H),1.45 (s, 9H).

Step 2—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]propyl]carbamate

To a mixture of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]prop-2-ynoxy]propyl]carbamate(868 mg, 1.90 mmol) in THF (30 mL) was added Pd/C (200 mg, 10 wt %) andPd(OH)₂/C (200 mg, 10 wt %). The suspension was degassed under vacuumand purged with H₂ gas 3 times. The mixture was stirred under H₂ (15psi) at 20° C. for 12 hours. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (835 mg, 95% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.22 (s, 1H), 7.66-7.59 (m, 1H), 7.27 (s, 1H), 7.16 (s, 1H), 7.05 (s,1H), 5.37-5.32 (m, 1H), 2.98 (d, J=6.4 Hz, 2H), 2.71-2.64 (m, 5H), 2.34(d, J=1.6 Hz, 3H), 2.16-2.15 (m, 2H), 1.88-1.72 (m, 2H), 1.66-1.54 (m,2H), 1.37 (s, 9H).

Step3—3-[6-[3-(3-Aminopropoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]propyl]carbamate (680 mg, 1.47 mmol) in DCM (20 mL) was addedHCl/dioxane (4 M, 0.7 mL). The reaction mixture was stirred at 20° C.for 2 hours. On completion, the reaction mixture was concentrated invacuo to give title compound (580 mg, 98% yield) as a white solid. LC-MS(ESI⁺) m/z 362.1 (M+H)⁺.

3-[7-[3-[3-(Methylamino)propoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate QA)

Step 1—Tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate

To a solution of tert-butyl N-methyl-N-(3-prop-2-ynoxypropyl)carbamate(1.05 g, 4.61 mmol, Intermediate PO) and3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (500 mg, 1.54mmol, Intermediate JF) in DMF (10 mL) was added Pd(PPh₃)₂Cl₂ (215 mg,307 umol), CuI (58.5 mg, 307 umol) and Cs₂CO₃ (2.51 g, 7.69 mmol). Thereaction mixture was stirred at 80° C. for 2 hr under N₂. On completion,the mixture was filtered, and the filtrate was concentrated in vacuo togive a residue. The residue was purified by reverse phase (0.1% FAcondition) to give the title compound (440 mg, 60% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 7.35-7.28 (m, 1H),7.28-7.19 (m, 2H), 5.39 (dd, J=5.2, 12.8 Hz, 1H), 4.45 (s, 2H), 3.53 (t,J=6.4 Hz, 2H), 3.23 (t, J=6.8 Hz, 2H), 2.94-2.82 (m, 1H), 2.77 (s, 3H),2.71-2.60 (m, 2H), 2.22-2.13 (m, 1H), 1.81-1.68 (m, 2H), 1.37 (s, 9H);LC-MS (ESI⁺) m/z 372.1 (M+H−100)⁺.

Step 2—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]propyl]-N-methyl-carbamate

To a solution of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate (440 mg, 933 umol) in THF (10 mL) was addedPd(OH)₂/C (150 mg, 10 wt %) and Pd/C (150 mg, 10 wt %). The reactionmixture was stirred at 25° C. under H₂ (15 psi) for 12 hours. Oncompletion, the residue was filtered and the filtrate was concentratedin vacuo to give the title compound (400 mg, 90% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s,1H), 7.18-7.06 (m, 2H), 7.01 (d, J=7.2 Hz, 1H), 5.35 (dd, J=5.2, 12.8Hz, 1H), 3.42-3.38 (m, 2H), 3.35-3.30 (m, 2H), 3.21 (t, J=7.2 Hz, 2H),2.93-2.83 (m, 1H), 2.78-2.71 (m, 5H), 2.70-2.61 (m, 2H), 2.19-2.10 (m,1H), 1.91-1.79 (m, 2H), 1.74-1.63 (m, 2H), 1.37 (s, 9H); LC-MS (ESI⁺)m/z 489.2 (M+Na)⁺.

Step3—3-[7-[3-[3-(Methylamino)propoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]propyl]-N-methyl-carbamate(400 mg, 841 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL). Thereaction mixture was stirred at 20° C. for 1 hr. On completion, themixture was concentrated in vacuo to give the title compound (340 mg,98% yield, HCl) as a white solid. LC-MS (ESI⁺) m/z 376.2 (M+H)⁺.

2-Tert-butylN-[2-[2-[2-(2-oxo-3H-benzimidazol-1-yl)ethoxy]ethoxy]ethyl]carbamate(Intermediate OB)

Step 1—Tert-ButylN-[2-[2-[2-(2-nitroanilino)ethoxy]ethoxy]ethyl]carbamate

To a mixture of 1-fluoro-2-nitro-benzene (2.84 g, 20.1 mmol, 2.12 mL,CAS #127723-77-7) and tert-butylN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (5.00 g, 20.1 mmol, CAS#153086-78-3) in DMF (50 mL) was added K₂CO₃ (8.35 g, 60.4 mmol). Thereaction mixture was stirred at 80° C. for 2 hours. On completion, thereaction mixture was diluted with water (50 mL) and extracted with EA(2×100 mL). The combined organic layers was dried over Na₂SO₄, filteredand concentrated in vacuo to give the title compound (7.40 g, 99% yield)as red oil. ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s, 1H), 8.20-8.14 (m, 1H),7.48-7.40 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 6.71-6.61 (m, 1H), 5.07 (s,1H), 3.80 (t, J=5.2 Hz, 2H), 3.71-3.62 (m, 4H), 3.59-3.49 (m, 4H),3.88-3.27 (m, 2H), 1.43 (s, 9H).

Step 2—Tert-butylN-[2-[2-[2-(2-aminoanilino)ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-(2-nitroanilino)ethoxy]ethoxy]ethyl]carbamate (7.00 g, 18.9mmol) in THF (100 mL) was added Pd/C (3.00 g, 10 wt %). The reactionmixture was stirred at 25° C. for 12 hours under H₂ (15 Psi) atmosphere.On completion, the reaction mixture was filtered and concentrated invacuo to give the title compound (6.40 g, 99% yield) as red oil. ¹H NMR(400 MHz, CDCl₃) δ 6.84-6.78 (m, 1H), 6.74-6.64 (m, 3H), 5.32 (s, 1H),3.76 (t, J=5.2 Hz, 2H), 3.67-3.60 (m, 4H), 3.54 (t, J=5.2 Hz, 2H),3.35-3.27 (m, 4H), 1.45 (s, 9H).

Step 3—2-Tert-ButylN-[2-[2-[2-(2-oxo-3H-benzimidazol-1-yl)ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-(2-aminoanilino)ethoxy]ethoxy]ethyl]carbamate (6.70 g, 19.7mmol) in THF (100 mL) was added CDI (11.8 g, 73.0 mmol) and DIPEA (9.44g, 73.0 mmol, 12.7 mL). The mixture was stirred at 25° C. for 3 hours.On completion, the reaction mixture was diluted with water (50 mL) andextracted with EA (2×100 mL). The combined organic layers was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography to give the title compound(7.20 g, 99% yield) as red oil. ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s,1H), 7.02-6.94 (m, 4H), 6.74 (s, 1H), 3.93 (t, J=5.6 Hz, 2H), 3.65 (t,J=5.6 Hz, 2H), 3.52-3.41 (m, 4H), 3.32 (t, J=6.0 Hz, 2H), 3.10-2.94 (m,2H), 1.36 (s, 9H).

3-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate OC)

Step 1—Tert-ButylN-[2-[2-[2-[3-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-2-oxo-benzimidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-(2-oxo-3H-benzimidazol-1-yl)ethoxy]ethoxy]ethyl]carbamate(3.00 g, 8.21 mmol, Intermediate QB) in THF (50 mL) was added t-BuOK(1.38 g, 12.3 mmol), the mixture was stirred at 0° C. for 0.5 hour. Then[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (4.70 g, 12.3 mmol, Intermediate IQ) in THF (20 mL) was addedto the mixture. The reaction mixture was stirred at 0° C. for 2 hoursunder N₂ atmosphere. On completion, the reaction mixture was dilutedwith water (30 mL) and extracted with EA (2×200 mL). The combinedorganic layers was dried over Na₂SO₄, filtered and concentrated in vacuoto give a residue. The residue was purified by prep-HPLC (0.1% FAcondition) to give the title compound (4.00 g, 81% yield) as brown oil.¹H NMR (400 MHz, DMSO-d₆) δ 7.26 (d, J=7.6 Hz, 1H), 7.21 (d, J=8.8 Hz,2H), 7.09-7.04 (m, 1H), 7.02-6.95 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.70(s, 1H), 5.57-5.48 (m, 1H), 4.87-4.73 (m, 2H), 4.02-3.98 (m, 2H), 3.72(s, 3H), 3.68 (d, J=5.2 Hz, 2H), 3.54-3.49 (m, 2H), 3.46-3.41 (m, 2H),3.33 (s, 2H), 3.12-3.05 (m, 1H), 3.04-2.97 (m, 2H), 2.86-2.69 (m, 2H),2.10-2.01 (m, 1H), 1.36 (s, 9H).

Step2—3-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[2-[2-[2-[3-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-2-oxo-enzimidazol-1-yl]ethoxy]ethoxy]ethyl]carbamate(1.00 1.68 mmol) in DCM (10 mL) was added TFA (7.70 g, 67.5 mmol, 5.00mL). The mixture was stirred at 25° C. for 0.5 hour. Then CF₃SO₃H (4.25g, 28.3 mmol, 2.50 mL) was added to the mixture. The mixture was stirredat 25° C. for 30 hours. On completion, the reaction mixture was dilutedwith water (20 mL) and basified with saturated aqueous K₂CO₃ tillpH=8-9, then the solution was extracted with DCM (3×50 mL). The aqueousphase was concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (0.1% HCl condition) to give the title compound(330 mg, 52% yield) as brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s,1H), 7.74 (s, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.15-7.09 (m, 1H), 7.09-7.00(m, 2H), 5.41-5.33 (m, 1H), 4.01 (t, J=5.4 Hz, 2H), 3.70 (t, J=5.4 Hz,2H), 3.58-3.55 (m, 2H), 3.53-3.50 (m, 4H), 2.94-2.85 (m, 3H), 2.78-2.63(m, 2H), 2.06-1.97 (m, 1H).

Benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(Intermediate QD)

Step 1—(S)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate

To a stirred solution Boc-D-prolinamide (50.0 g, 234.0 mmol) in CH₂Cl₂(25 mL) at rt was added Lawesson's reagent (62.2 g, 140.0 mmol). Themixture was stirred overnight, then washed with NaHCO₃ (sat., 500 mL).The organic layer was washed with brine, and dried over anhydrousNa₂SO₄. The oily residue was purified by column chromatography on silicagel, eluted with a 0-10 percent MeOH in CH₂Cl₂ gradient, to afford thetitle compound (42 g, 78% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 9.51 (s, 1H), 9.08 (m, 1H), 4.41 (dd, J=8.4, 3.3 Hz, 1H),3.47-3.46 (m, 1H), 3.27 (s, 1H), 2.27-2.09 (m, 1H), 1.92-1.65 (m, 3H),1.37 (m, 9H).

Step 2—Ethyl(S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate

Ethyl bromopyruvate (4.15 g, 21.3 mmol) was added dropwise via syringeto a mixture of (S)-tert-butyl 2-carbamothioylpyrrolidine-1-carboxylate(3.5 g, 15.2 mmol) and potassium bicarbonate (50.5 g, 504 mmol) in 35 mLof dimethoxyethane at 23c° C. The resulting mixture was stirredvigorously for 25 minutes, and then the mixture was cooled to 0° C. Amixture of trifluoroacetic anhydride (TFAA) (3.19 g, 15.2 mmol, 1equiv.) and 2,4,6-collidine (2.94 g, 24.3 mmol, 1.6 equiv.) was thenadded dropwise via canula to the yellow mixture prepared above at 0° C.Following this addition, an additional three portions of neat TFAA (3.19g, 15.2 mmol, 1 equiv.) and 2,4,6-collidine (2.94 g, 24.3 mmol, 1.6equiv.) were prepared and added in sequence dropwise via canula to theyellow reaction mixture at 0° C. The resulting yellow mixture wasstirred vigorously at 0° C. for 3 h. Then water (1,000 mL) was added andthe solution was extracted with dichloromethane (2×50 mL). The organicphases were combined, washed with 0.5 N aqueous HCl (100 mL), washedwith brine (100 mL), and dried over anhydrous sodium sulfate. Thesolution was filtered and concentrated to afford a light yellow solid.This solid was purified by flash column chromatography on silica gel(1:9 to 2:3 ethyl acetate:hexanes) providing a light yellow solid. Thissolid was triturated with ether (20 mL) to afford the title compound asa white solid (2.2 g, 44% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d,J=9.8 Hz, 1H), 5.08 (d, J=7.3 Hz, 1H), 4.33-4.25 (m, 2H), 3.53-3.34 (m,2H), 2.38-2.27 (m, 1H), 2.04-1.99 (m, 1H), 1.93-1.79 (m, 2H), 1.43 (s,6H), 1.30 (t, J=7.1 Hz, 3H), 1.24 (s, 3H). LC/MS (ESI, m/z):[M+1]⁺=327.3.

Step3—(S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylicacid

A solution of (S)-ethyl2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylate (14.5g, 44.5 mmol, 1 equiv.) in tetrahydrofuran (60 mL) was added to asolution of sodium hydroxide (5.33 g, 134.5 mmol, 3 equiv.) in water (40mL) at 23° C. The resulting mixture was stirred vigorously at 23° C. for3 h. Then the mixture was concentrated to 20 mL. The concentratedmixture was cooled to 0° C. and the pH was adjusted to 3 by the additionof concentrated HCl solution dropwise. A lot of white solid was formedand the solid was collected by filtration to provide the title compoundas a white solid (10.4 g, 74% yield). LC/MS (ESI, m/z): [M+1]⁺=299.4.

Step 4—tert-butyl(S)-2-(4-(methoxy(methyl)carbamoyl)thiazol-2-yl)pyrrolidine-1-carboxylate

(S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)thiazole-4-carboxylic acid(22.6 g, 75.8 mmol), O,N-dimethylhydroxylamine hydrochloride (11.9 g,122.7 mmol), diisopropyl ethyl amine (45.0 mL, 243 mmol) and HATU (46.2g, 122.0 mmol) in DMF (200 mL) were stirred at rt for 12 hours. Thereaction mixture was quenched with water, and the layers were separated.The aqueous layer was extracted with EtOAc (100 mL×3), and the combinedorganic layers were dried, filtered and concentrated. The crude productwas purified via column chromatography on silica gel, eluting withhexanes/ethyl acetate (1:1) to give the title compound as an oil (23.0g, 89% yield). LC/MS (ESI, m/z): [M+1]⁺=342.2. ¹H NMR (400 MHz, DMSO-d₆)δ 8.11 (s, 1H), 5.08 (m, 1H), 3.72 (s, 3H), 3.52-3.35 (m, 2H), 3.29 (s,3H), 2.32 (m, 1H), 2.06 (m, 1H), 1.96-1.77 (m, 2H), 1.50-1.20 (d, 9H).

Step 5—(S)-tert-butyl2-(4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)thiazol-2-yl)pyrrolidine-1-carboxylate

To a solution of tert-butyl(3-iodophenoxy)dimethylsilane (6.9 g, 20.6mmol) in THF (50 mL) was added isopropylmagnesium chloride solution(9.27 mL, 2.0 M in THF) dropwise at −10° C. under N₂. The reactionmixture was stirred at 0° C. for 30 min. Then this resulting mixture,which formed (3-((tert-butyldimethylsilyl)oxy)phenyl)magnesium iodide,was added dropwise via syringe to a solution of the weinreb amidetert-butyl(S)-2-(4-(methoxy(methyl)carbamoyl)thiazol-2-yl)pyrrolidine-1-carboxylate(3.9 g, 11.4 mmol) in THF (10 mL) at 0° C. The mixture was stirred at 0°C. for 30 min then warmed up to rt and stirred for 4 h. The mixture wasthen cooled to −5° C. and quenched with saturated ammonium chloridesolution (20 mL). The mixture was partitioned between water (30 mL) andethyl acetate (100 mL). The organic phase was separated and the aqueousphase was further extracted with ethyl acetate (3×100 mL). The organicphases were combined, washed with brine (50 mL) and dried over anhydroussodium sulfate. The dried solution was filtered and concentrated to givea light yellow oil. This oil was purified by flash column chromatographyon silica gel (1:30 to 1:10 ethyl acetate:hexanes) providing the titlecompound as a colorless oil (5.13 g, 92.1%). ¹H NMR (400 MHz, CDCl₃) δ8.10 (s, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.71-7.66 (m, 1H), 7.34 (t, J=7.9Hz, 1H), 7.07 (d, J=7.0 Hz, 1H), 5.30-5.19 (m, 1H), 3.66-3.41 (m, 2H),2.42-2.19 (m, 2H), 2.01-1.90 (m, 2H), 1.50 (s, 3H), 1.35 (s, 6H),1.02-0.98 (m, 9H), 0.28-0.14 (m, 6H); LC/MS (ESI, m/z): [M+1]⁺=489.5.

Step6—(S)-(3-((tert-butyldimethylsilyl)oxy)phenyl)(2-(pyrrolidin-2-yl)thiazol-4-yl)methanone

To a solution of (S)-tert-butyl2-(4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)thiazol-2-yl)pyrrolidine-1-carboxylate(12.0 g, 20.5 mmol) in 1,4-dioxane (60 mL) was added HCl-dioxane (40 mL)(4 M in dioxane) dropwise. The reaction mixture was stirred at rt for 3h. The reaction mixture concentrated in vacuo and used directly withoutfurther purification to afford(S)-(3-hydroxyphenyl)(2-(pyrrolidin-2-yl)thiazol-4-yl)methanone HCl salt(8.0 g). To a solution of(S)-(3-hydroxyphenyl)(2-(pyrrolidin-2-yl)thiazol-4-yl)methanone HCl salt(8.00 g, 25.7 mmol) in DCM (80 mL) was added imidazole (5.2 g, 57.2mmol) slowly at 0° C. Then TBSCl (3.89 g, 34.3 mmol, in 20 mL DCM) wasadded slowly at 0° C. The resulting mixture was stirred at rt for 130min. The reaction mixture was quenched with water, extracted with ethylacetate (3×100 mL), washed with brine (50 mL) and dried over anhydroussodium sulfate. The solution was filtered, concentrated, and purified byflash column chromatography on silica gel (1:100 to 1:40 methanol/DCM)to give the title compound as a yellow oil (8.0 g, 84% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.38 (s, 1H), 7.71-7.64 (m, 2H), 7.43 (t, J=8.0 Hz,1H), 7.14 (ddd, J=8.0, 2.4, 1.1 Hz, 1H), 4.51 (dd, J=8.3, 4.9 Hz, 1H),3.56 (s, 1H), 3.00-2.89 (m, 2H), 2.27-2.10 (m, 1H), 1.75-1.70 (m, 1H),1.77-1.65 (m, 2H), 0.97 (s, 9H), 0.22 (s, 6H).

Step 7—Benzyl((S)-1-(((S)-2-((S)-2-(4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

In a 250-mL round-bottom flask, was placed(S)-(3-((tert-butyldimethylsilyl)oxy)phenyl)(2-(pyrrolidin-2-yl)thiazol-4-yl)methanone(7.5 g, 19.3 mmol),(S)-2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-2-cyclohexylaceticacid (9.5 g, 25.1 mmol, Intermediate UU), and 4-methylmorpholine (3.90g, 38.60 mmol) in EtOAc (100 mL) at 0° C. DMT-MM (6.94 g, 25.1 mmol) wasthen added and the resulting solution was stirred for 3 h at 0° C. ThenH₂O (40 mL) was added, and the resulting solution was extracted withEtOAC (3×50 mL). The combined organic layers were washed with 50 mL ofbrine, dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was applied onto a silica gel column eluting withethyl acetate/petroleum ether (1:2) to give the title compound as ayellow solid. (7.3 g, 60% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s,1H), 7.95 (d, J=39.4 Hz, 1H), 7.74-7.63 (m, 2H), 7.43 (t, J=7.9 Hz, 1H),7.35-7.31 (m, 5H), 7.16 (dd, J=8.0, 2.5 Hz, 1), 5.37 (dd, J=7.6, 2.2 Hz,1), 5.08-5.01 (m, 1), 4.66 (d, J=6.6 Hz, 1), 4.37 (t, J=7.5 Hz, 1H),3.83-3.75 (m, 2H), 2.83 (s, 3H), 2.33-2.14 (m, 2H), 2.07-1.98 (m, 2H),1.67-1.48 (m, 6H), 1.25 (s, 3H), 1.07-0.89 (m, 14H), 0.22 (s, 6H). LC/MS(ESI, m/z): [M+1]⁺=747.6.

Step 8—Benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a stirred solution of benzyl((S)-1-(((S)-2-((S)-2-(4-(3-((tert-butyldimethylsilyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(5.0 g, 6.68 mmol) in THF (20 mL) was added TBAF (8.0 mL, 8.0 mmol) art. The reaction mixture was stirred at rt for 4 h. Then H₂O (20 mL) wasadded and the mixture was extracted with EtOAc (50 mL×2). The combinedorganic layer was washed with brine, dried and concentrated in vacuo.The mixture was purified via column chromatography (DCM/EtOAc=5%-80%) togive the title compound (3.2 g, 76% yield) as a yellow solid. ¹H NMR(400 MHz, MeOD-d₄) δ 8.26 (s, 1H), 7.59-7.53 (m, 1H), 7.51 (dd, J=2.3,1.7 Hz, 1H), 7.37-7.28 (m, 6H), 7.05 (ddd, J=8.1, 2.6, 0.9 Hz, 1H),5.50-5.39 (m, 1H), 5.13 (s, 2H), 4.69 (s, 1H), 4.54-4.38 (m, 1H),4.02-3.93 (m, 1H), 3.90-3.86 (m, 1H), 2.94 (s, 3H), 2.23-2.10 (m, 4H),1.72-1.56 (m, 6H), 1.37 (d, J=5.2 Hz, 3H), 1.16-0.88 (m, 5H); LC-MS(ESI⁺): m/z 633.5 (M+H)⁺.

BenzylN-[(1S)-2-[[(1S)-2-[(2S)-2-[4-[3-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxylethoxy]ethoxy]ethoxy]ethoxy]benzoyl]thiazol-2-yl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(Intermediate OE)

Step 1—Benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl]oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.3 g, 2.06 mmol, Intermediate QD) in CH₃CN (100 mL) was added2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl4-methylbenzenesulfonate (1.32 g, 2.47 mmol, Intermediate 00) and K₂CO₃(340.9 mg, 2.47 mmol) at rt. Then the reaction mixture was stirred at80° C. for 12 h. The reaction mixture solvent was removed under reducedpressure. The residue was purified via column chromatography(EtOAc/Petroleum ether) to give the title compound (1.71 g, 84% yield)as a pale yellow oil. LC/MS (ESI, m/z): [M+1]⁺=997.56.

Step 2—Benzyl((S)-1-(((S)-2-((S)-2-(4-(3-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate2,2,2-trifluoroacetate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.6 g, 1.61 mmol) in DCM (30 mL) was added TFA (30 mL) and the reactionmixture was stirred at rt for 3 h. Then the reaction mixture solvent wasremoved under reduced pressure and the residue was purified via reversephase column chromatography (ACN/H₂O) to give the title compound (1.4 g,86% yield) as a pale yellow oil. ¹H NMR (400 MHz, MeOD) δ: 8.32 (s, 1H),7.86-7.67 (m, 2H), 7.45 (t, J=7.9 Hz, 1H), 7.41-7.13 (m, 6H), 5.62-5.47(m, 1H), 5.13 (s, 2H), 4.73-4.68 (m, 1H), 4.59-4.34 (m, 1H), 4.24-4.22(m, 2H), 4.07-3.79 (m, 4H), 3.79-3.52 (m, 18H), 3.19-3.05 (m, 2H),2.94-2.77 (m, 3H), 2.62-1.91 (m, 4H), 1.88-1.49 (m, 6H), 1.37-1.35 (m,3H), 1.23-0.82 (m, 5H). LC/MS (ESI, m/z): [M+1]⁺=896.57.

BenzylN-[(1S)-2-[[(1S)-2-[(2S)-2-[4-[3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]benzoyl]thiazol-2-yl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(Intermediate OF)

Step 1—Benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.50 g, 2.38 mmol, Intermediate QD) in CH₃CN (100 mL) was added2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl4-methylbenzenesulfonate (1.30 g, 3.09 mmol, Intermediate LD) and K₂CO₃(346.4 mg, 2.51 mmol) at rt. The reaction mixture was stirred at 80° C.for 12 hours. The reaction mixture was then concentrated under reducedpressure. The residue was purified via column chromatography on silicagel (EtOAc/petroleum ether-1/1-EA) to give the title compound (1.80 g,80% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H),7.97 (d, J=40.8 Hz, 1H), 7.69-7.64 (m, 2H), 7.46 (t, J=7.9 Hz, 1H),7.39-7.29 (m, 5H), 7.26 (dd, J=8.2, 1.9 Hz, 1H), 6.73 (t, J=5.1 Hz, 1H),5.40-5.37 (m, 1H), 5.09-5.06 (m, 2H), 4.70-4.65 (m, 1H), 4.38 (t, J=7.5Hz, 1H), 4.23-4.12 (m, 2H), 3.85-3.73 (m, 4H), 3.62-3.59 (m, 2H),3.55-3.47 (m, 6H), 3.36 (t, J=6.2 Hz, 2H), 3.05 (q, J=5.9 Hz, 2H), 2.84(s, 3H), 2.28-2.14 (m, 2H), 2.08-2.01 (m, 2H), 1.66-1.44 (m, 6H), 1.36(s, 9H), 1.26 (br s, 3H), 1.09-0.86 (m, 5H). LC/MS (ESI, m/z):[M+1]⁺=908.6.

Step 2—Benzyl((S)-1-(((S)-2-((S)-2-(4-(3-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethoxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-yl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.8 g, 1.47 mmol) in DCM (30 mL) was added TFA (30 mL) and the reactionmixture was stirred at rt for 3 h. The reaction mixture was concentratedunder reduced pressure to give the title compound (1.8 g, 100% yield,TFA salt) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H),7.80 (br s, 1H), 7.76-7.70 (m, 2H), 7.44 (t, J=7.9 Hz, 1H), 7.38-7.30(m, 5H), 7.26-7.20 (m, 1), 5.47-5.46 (m, 1), 5.13 (s, 2H), 4.73-4.65 (m,1), 4.53-4.40 (m, 1), 4.22 (dd, J=5.3, 3.8 Hz, 2H), 4.00-3.94 (m, 1H),3.89-3.86 (m, 3H), 3.76-3.72 (m, 2H), 3.70-3.66 (m, 8H), 3.12-3.08 (m,2H), 2.94 (s, 3H), 2.40-2.19 (m, 3H), 2.17-2.09 (m, 1H), 1.72-1.57 (m,6H), 1.36 (d, J=7.2 Hz, 3H), 1.19-0.94 (m, 5H). LC/MS (ESI, m/z):[M+1]⁺=808.6.

BenzylN-[(1S)-2-[[(1S)-2-[(2S)-2-[4-[3-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]benzoyl]thiazol-2-yl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(Intermediate QG)

Step 1—Benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.32 g, 2.09 mmol, Intermediate QD) in CH₃CN (100 mL) was added2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl4-methylbenzenesulfonate (1.23 g, 2.51 mmol, Intermediate ON) and K₂CO₃(346.4 mg, 2.51 mmol) at rt. Then the reaction mixture was stirred at80° C. for 12 h. The reaction mixture was then concentrated underreduced pressure. The residue was purified via column chromatography onsilica gel (EtOAc/petroleum ether) to give the title compound (1.68 g,85% yield) as a pale yellow oil. LC/MS (ESI, m/z): [M+1]⁺=953.7.

Step 2—benzyl((S)-1-(((S)-2-((S)-2-(4-(3-((14-amino-3,6,9,12-tetraoxatetradecyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate2,2,2-trifluoroacetate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11,14,17-pentaoxa-5-azanonadecan-19-yl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.4 g, 1.47 mmol) in DCM (30 mL) was added TFA (30 mL) and the reactionmixture was stirred at rt for 3 h. Then the reaction mixture wasconcentrated under reduced pressure and the residue was purified viareverse phase column chromatography (ACN/H₂O) to give the title compound(1.2 g, 84% yield) as a colorless oil. ¹H NMR (400 MHz, CD₃OD) δ: 8.33(s, 1H), 7.90-7.68 (m, 3H), 7.50-7.40 (m, 1H), 7.40-7.19 (m, 5H),5.67-5.30 (m, 1H), 5.13 (s, 2H), 4.73-4.67 (m, 1H), 4.50-4.40 (m, 1H),4.29-4.12 (m, 2H), 4.05-3.79 (m, 4H), 3.78-3.52 (m, 14H), 3.10-3.07 (m,2H), 2.94 (s, 3H), 2.57-1.95 (m, 4H), 1.85-1.46 (m, 6H), 1.40-1.29 (m,3H), 1.27-0.86 (m, 5H). LC/MS (ESI, m/z): [M+1]⁺=852.7.

BenzylN-[(1S)-2-[[(1S)-2-[(2S)-2-[4-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]benzoyl]thiazol-2-yl]pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(Intermediate OH)

Step 1—Benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.30 g, 2.05 mmol, Intermediate QD) in CH₃CN (25 mL) was added2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl4-methylbenzenesulfonate (1.20 g, 2.46 mmol, Intermediate UV) and K₂CO₃(368 mg, 2.67 mmol) at rt. The reaction mixture was stirred at 80° C.for 12 hours. The reaction mixture was concentrated under reducedpressure. The residue was purified via column chromatography on silicagel (EtOAc/Petroleum ether=1/1-EA) to give the title compound (1.30 g,68% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.32 (s, 1H),7.73-7.71 (m, 2H), 7.43 (t, J=8.0 Hz, 1H), 7.39-7.29 (m, 5H), 7.26-7.20(m, 1H), 5.47-5.46 (m, 1H), 5.13 (s, 2H), 4.69 (br s, 1H), 4.52-4.41 (m,1H), 4.22-4.18 (m, 2H), 4.00-3.93 (m, 1H), 3.89-3.87 (m, 3H), 3.73-68(m, 2H), 3.66-3.61 (m, 2H), 3.52-3.49 (m, 2H), 3.23-3.19 (m, 2H), 2.94(s, 3H), 2.36-2.20 (m, 3H), 2.18-2.06 (m, 1H), 1.76-1.50 (m, 6H), 1.41(s, 9H), 1.36 (d, J=7.2 Hz, 3H), 1.17-0.96 (m, 5H). LC/MS (ESI, m/z):[M+1]⁺=864.6.

Step 2—Benzyl((S)-1-(((S)-2-((S)-2-(4-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-((2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.2 g, 1.39 mmol) in DCM (5 mL) was added TFA (5 mL) and the reactionmixture was stirred at rt for 3 h. The reaction mixture was concentratedunder reduced pressure to give the title compound (1.2 g, 100% yield,TFA salt) as a light yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H),7.79-7.71 (m, 2H), 7.45 (t, J=8.0 Hz, 1H), 7.38-7.28 (m, 5H), 7.25-7.22(m, 1H), 5.47-5.46 (m, 1H), 5.13 (s, 2H), 4.73-4.64 (m, 1H), 4.52-4.40(m, 1H), 4.24-4.21 (m, 2H), 4.01-3.94 (m, 1H), 3.90-3.88 (m, 3H),3.77-3.74 (m, 2H), 3.72-3.69 (m, 4H), 3.11 (t, J=4.8 Hz, 2H), 2.94 (s,3H), 2.39-2.11 (m, 4H), 1.75-1.54 (m, 6H), 1.36 (t, J=8.0 Hz, 3H),1.16-0.99 (m, 5H). LC/MS (ESI, m/z): [M+1]⁺=764.6.

[3-Methyl-5-[3-[3-(methylamino)propoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate 01)

Step 1—Tert-ButylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate

To a solution of tert-butyl N-methyl-N-(3-prop-2-ynoxypropyl)carbamate(604 mg, 2.66 mmol, Intermediate PO) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (450mg, 1.33 mmol, Intermediate HN) in DMF (10 mL) was added Pd(PPh₃)₂Cl₂(186 mg, 266 umol), CuI (50.6 mg, 266 umol) and Cs₂CO₃ (2.17 g, 6.65mmol). The reaction mixture was stirred at 80° C. for 2 hr under N2. Oncompletion, the mixture was filtered, and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.10% FA condition) to give the title compound (550 mg, 85% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.65-7.52 (m,3H), 5.39 (dd, J=5.6, 12.8 Hz, 1H), 4.45-4.18 (m, 2H), 3.62-3.44 (m,2H), 3.22 (t, J=7.2 Hz, 2H), 2.92-2.83 (m, 1H), 2.80-2.59 (m, 7H),2.08-2.00 (m, 1H), 1.77-1.70 (m, 2H), 1.38 (s, 9H); LC-MS (ESI⁺) m/z507.1 (M+Na)⁺.

Step 2—Tert-ButylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]propyl]-N-methyl-carbamate

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate(530 mg, 1.09 mmol) in THF (10 mL) was added Pd(OH)₂/C (200 mg, 10 wt %)and Pd/C (200 mg, 10 wt %). The reaction mixture was stirred at 25° C.under H₂ (15 Psi) for 12 hrs. On completion, the residue was filteredand the filtrate was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 38%-65%, 9min) to give the title compound (300 mg, 56% yield) as yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.05-6.98 (m, 2H), 6.87 (d,J=8.0 Hz, 1H), 5.33 (dd, J=5.6, 12.8 Hz, 1H), 3.36-3.33 (m, 4H), 3.32(s, 3H), 3.22 (t, J=7.2 Hz, 2H), 2.95-2.85 (m, 1H), 2.77 (s, 3H),2.73-2.60 (m, 4H), 2.03-1.98 (m, 1H), 1.86-1.78 (m, 2H), 1.73-1.69 (m,2H), 1.38 (s, 9H); LC-MS (ESI⁺) m/z 389.2 (M+H−100)⁺.

Step3—3-[3-Methyl-5-[3-[3-(methylamino)propoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy] propyl]-N-methyl-carbamate (50.0 mg, 102 umol) in DCM (3 mL)was added HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at25° C. for 2 hrs. On completion, the mixture was concentrated in vacuoto give the title compound (40.0 mg, 92% yield, HCl) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.06-6.97 (m, 2H), 6.90-6.84(m, 1H), 5.34 (dd, J=5.2, 12.8 Hz, 1H), 3.56 (s, 2H), 3.43 (t, J=6.0 Hz,2H), 3.32 (s, 3H), 2.96-2.86 (m, 3H), 2.72-2.58 (m, 4H), 2.56-2.52 (m,3H), 2.02-1.97 (m, 1H), 1.90-1.78 (m, 4H); LC-MS (ESI⁺) m/z 389.2(M+H)⁺.

Tert-Butyl (2-methyl-4-(prop-2-yn-1-yloxy)butan-2-yl)carbamate(Intermediate OJ)

Step 1—Tert-Butyl (4-hydroxy-2-methylbutan-2-yl)carbamate

To a solution of 3-amino-3-methylbutan-1-ol (4.0 g, 38.8 mmol, CAS#42514-50-1) and TEA (3.92 g, 38.8 mmol, 5.4 mL) in THF (50 mL) addeddropwise (Boc)₂O (9.31 g, 9.8 mL, 42.6 mmol) at 20° C. and the mixturewas stirred at 20° C. for 16 hours. Once completion, the reactionmixture was quenched by water (15 mL), and then extracted with EA (3×30mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂, PE/EA=10:1) to give the title compound(1.50 g, 19% yield) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ4.90 (s, 1H), 3.76 (q, 2H), 2.04 (s, 1H), 1.88 (t, J=6.4 Hz, 2H), 1.43(s, 9H), 1.32 (s, 6H).

Step 2—Tert-Butyl (2-methyl-4-(prop-2-yn-1-yloxy)butan-2-yl)carbamate

To a solution of tert-butyl (4-hydroxy-2-methylbutan-2-yl)carbamate(1.40 g, 6.89 mmol) and 3-bromoprop-1-yne (1.23 g, 10.3 mmol) in THF (20mL) was added KI (171 mg, 1.03 mmol), TBAI (152 mg, 0.41 mmol) and KOH(463 mg, 8.26 mmol) at 30° C. Then the mixture was stirred at 30° C. for16 hours. On completion, the reaction mixture was filtered and thefiltrate was concentrated in vacuo to give the residue. The residue waspurified by column chromatography (SiO₂, PE/EA=30:1) to give the titlecompound (1.40 g, 84% yield) as a light yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 4.84 (s, 1H), 4.12 (d, J=2.4 Hz, 2H), 3.62 (t, J=6.4 Hz, 2H),2.42 (t, J=2.4 Hz, 1H), 1.91 (t, J=6.4 Hz, 2H), 1.42 (s, 9H), 1.31 (s,6H).

3-[7-[3-(3-Amino-3-methyl-butoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate QK)

Step 1—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]-1,1-dimethyl-propyl]carbamate

To a solution of3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (320 mg, 0.98mmol, Intermediate JF) and tert-butyl(2-methyl-4-(prop-2-yn-1-yloxy)butan-2-yl)carbamate (593 mg, 2.46 mmol,Intermediate QJ) in DMF (20 mL) was added Cs₂CO₃ (1.28 g, 3.94 mmol),CuI (37.49 mg, 0.2 mmol), Pd(PPh₃)₂Cl₂ (138 mg, 0.2 mmol) and 4Åmolecular sieves (80 mg) at 25° C. under N₂. Then the reaction mixturewas heated to 80° C. and stirred for 2 hours. On completion, thereaction mixture was quenched by addition of water (10 m)L, and thenextracted with EA (30 mL, 3×10 mL). The combined organic layers anddried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=2/1 to 1/1) to give the title compound (330 mg, 69%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H),7.25-7.19 (m, 1H), 7.13 (t, J=8.0 Hz, 1H), 6.82-6.75 (m, 1H), 5.08-5.01(m, 1H), 4.91 (s, 1H), 4.41 (s, 2H), 3.73 (t, J=6.4 Hz, 2H), 3.04-2.95(m, 1H), 2.91-2.66 (m, 2H), 2.40-2.27 (m, 1H), 1.97 (t, J=6.2 Hz, 2H),1.41 (s, 9H), 1.35 (s, 6H); LC-MS (ESI⁺) m/z 386.0 (M+H−100)⁺.

Step 2—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]-1,1-dimethyl-propyl]carbamate

To a mixture of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]-1,1-dimethyl-propyl]carbamate(130 mg, 0.27 mmol) in THF (15 mL) was added Pd/C (10 wt %) andPd(OH)₂/C (10 wt %) under N₂. The suspension was degassed under vacuumand purged with H₂ gas several times. The mixture was stirred at 25° C.for 16 hours under H₂ (15 psi). On completion, the reaction mixture wasfiltered and concentrated in vacuo to give the title compound (127 mg,85% yield) as a white solid. LC-MS (ESI⁺) m/z 390.2 (M+H−100)⁺.

Step3—3-[7-[3-(3-Amino-3-methyl-butoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]-1,1-dimethyl-propyl]carbamate(127 mg, 0.26 mmol) in DCM (5 mL) was added TFA (591 mg, 0.52 mmol, 0.38mL) at 25° C. The mixture was stirred at 25° C. for 60 min. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (126 mg, 96% yield, TFA) as light yellow oil. ¹H NMR (400MHz, CDCl₃) δ 9.05 (s, 1H), 7.13 (t, J=16 Hz, 1H), 7.03-6.98 (m, 1H),6.78 (d, J=8.0 Hz, 1H), 5.14-5.09 (m, 1H), 3.67 (t, J=5.6 Hz, 2H), 3.56(t, J=5.6 Hz, 2H), 2.99-2.71 (m, 6H), 2.37-2.33 (m, 1H), 2.04-1.96 (m,2H), 1.84 (t, J=5.6 Hz, 2H), 1.40 (s, 6H); LC-MS (ESI⁺) m/z 390.1(M+H)⁺.

2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl (4-nitrophenyl)carbonate (Intermediate OL)

To a solution of (4-nitrophenyl) carbonochloridate (711 mg, 3.53 mmol,CAS #7693-46-1) and tert-butylN-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (800 mg, 3.21 mmol, CAS#139135-92-7) in DCM (20 mL) was added TEA (812 mg, 8.02 mmol) at 0° C.The reaction mixture was stirred at this temperature for 1 hr. Oncompletion, the mixture was quenched with water (10 mL), andconcentrated in vacuo to give the title compound (1.2 g, 90% yield) as ayellow oil. LC-MS (ESI⁺) m/z 437.2 (M+Na)⁺.

3-[5-(Aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione(Intermediate OM)

Step 1—2-(2,6-Dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbonitrile

To a solution of 3-(5-bromo-1-oxo-isoindolin-2-yl) piperidine-2,6-dione(1.70 g, 5.26 mmol, Intermediate KC) and Zn(CN)₂ (370 mg, 3.16 mmol) inDMF (30.0 mL) was added Pd(PPh₃)₄ (607 mg, 526 umol). The mixture wasstirred at 100° C. for 3 hour under N₂. On completion, the mixture wasdiluted with H₂O (50 mL), then mixture was filtered and the solid wasdried in vacuo. The solid was triturated with PE:EA=5:1 (50 mL),filtered and the solid was dried in vacuo to give the title compound(1.10 g, 77% yield) as purple solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02(s, 1H), 8.16 (s, 1H), 8.01-7.90 (m, 2H), 5.20-5.09 (m, 1H), 4.59-4.37(m, 2H), 2.99-2.87 (m, 1H), 2.70-2.57 (m, 1H), 2.46-2.37 (m, 1H),2.11-1.98 (m, 1H).

Step 2—Tert-ButylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate

To a solution of2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindoline-5-carbonitrile (1.50 g, 5.57mmol) in THF (15.0 mL) and DMF (15.0 mL) was added (Boc)₂O (1.34 g, 6.13mmol) and Raney-Ni (750 mg, 8.75 mmol). The mixture was stirred at 30°C. for 40 hour under H₂ (50 psi). On completion, the mixture wasconcentrated in vacuo. The mixture was purified by silica gel column(PE:EA=1:2) to give the title compound (900 mg, 43% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 7.68 (d, J=7.6 Hz, 1),7.52 (t, J=6.0 Hz, 1), 7.45 (s, 1), 7.38 (d, J=7.6 Hz, 1), 5.17-5.03 (m,1H), 4.48-4.27 (m, 2H), 4.24 (d, J=6.0 Hz, 2H), 2.98-2.85 (m, 1H),2.65-2.55 (m, 1H), 2.44-2.31 (m, 1H), 2.06-1.96 (m, 1H), 1.40 (s, 9H).

Step 3—3-[5-(Aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate (200 mg, 535umol) in DCM (5.00 mL) was added HCl/dioxane (4.00 M, 5.00 mL). Themixture was stirred at rt for 0.5 hour. On completion, the mixture wasconcentrated in vacuo to give the title compound (160 mg, 90% yield,HCl) as white solid. LC-MS (ESI⁺) m/z 274.1 (M+H)⁺.

2-[2-(2-Aminoethoxy)ethoxy]ethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate(Intermediate ON)

Step1—2-[2-[2-(Tert-butoxycarbonylamino)ethoxy]ethoxy]ethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate

To a solution of3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (100 mg,323 umol, HCl, Intermediate QM) and2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl (4-nitrophenyl)carbonate (268 mg, 646 umol, Intermediate QL) in DMF (3 mL) was addedTEA (163 mg, 1.61 mmol) under N₂ atmosphere. The reaction mixture wasstirred at 25° C. for 1 h. On completion, the mixture was concentratedin vacuo. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (110 mg, 62% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.93-7.86 (m, 1), 7.70-7.65 (m, 1),7.47 (s, 1H), 7.42-7.36 (m, 1H), 6.82-6.72 (m, 1H), 5.14-5.06 (m, 1H),4.47-4.40 (m, 1H), 4.34-4.25 (m, 3H), 4.12-4.03 (m, 2H), 3.60-3.55 (m,2H), 3.50-3.47 (m, 4H), 3.38-3.36 (m, 2H), 3.05 (q, J=5.6 Hz, 2H),2.97-2.85 (m, 1H), 2.59-2.53 (m, 2H), 2.04-1.93 (m, 1H), 1.36 (s, 9H);LC-MS (ESI⁺) m/z 549.3 (M+H)⁺.

Step 2—2-[2-(2-Aminoethoxy)ethoxy]ethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]]carbamate

To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate(150 mg, 273 umol) in DCM (3 mL) was added HCV/dioxane (4 M, 5 mL). Thereaction mixture was stirred at 25° C. for 2 hrs. On completion, themixture was concentrated in vacuo to give the title compound (130 mg,98% yield, HCl) as a white solid. LC-MS (ESI⁺) m/z 449.2 (M+H)⁺.

2-(Tert-butoxycarbonylamino)ethyl (4-nitrophenyl) carbonate(Intermediate QO)

To a solution of tert-butyl N-(2-hydroxyethyl)carbamate (500 mg, 3.10mmol), (4-nitrophenyl)carbonochloridate (687 mg, 3.41 mmol) in DCM (20.0mL) was added TEA (784 mg, 7.75 mmol) at 0° C. The mixture was stirredat 0° C. for 1 hour. On completion, the mixture was concentrated invacuo to give the title compound (1.00 g, 90% yield) as yellow solid.LC-MS (ESI⁺) m/z 349.1 (M+Na)⁺.

2-AminoethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate(Intermediate QP)

Step 1—2-(Tert-butoxycarbonylamino)ethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate

To a solution of3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (200 mg,645 umol, HCl, Intermediate QM) and 2-(tertbutoxycarbonylamino)ethyl(4-nitrophenyl) carbonate (421 mg, 1.29 mmol, Intermediate QO) in DMF(10.0 mL) was added TEA (326 mg, 3.23 mmol). The reaction mixture wasstirred at 20° C. for 2 hrs. On completion, the mixture was concentratedin vacuo. The mixture was purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:26%-56%, 10 min) to give the title compound (160 mg, 53% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H), 7.82 (t, J=6.0 Hz,1H), 7.68 (d, J=8.0 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J=8.0 Hz, 1H),6.94-6.87 (m, 1H), 5.16-5.07 (m, 1H), 4.49-4.31 (m, 2H), 4.30 (d, J=6.4Hz, 2H), 3.99-3.90 (m, 2H), 3.18-3.09 (m, 2H), 2.97-2.89 (m, 1H),2.64-2.58 (m, 1H), 2.44-2.35 (m, 1H), 2.05-1.95 (m, 1H), 1.38 (s, 9H).

Step 2—2-AminoethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate

To a solution of 2-(tert-butoxycarbonylamino) ethylN-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate(140 mg, 304 umol) in DCM (2.00 mL) was added HCl/dioxane (4.00 M, 14.0mL). The mixture was stirred at 25° C. for 0.5 hr. On completion, themixture was concentrated in vacuo to give the title compound (120 mg,99% yield) as yellow solid. LC-MS (ESI⁺) m/z 361.2 (M+H)⁺.

3-[7-[3-(2-Aminoethoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate OR)

Step 1—Tert-ButylN-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]ethyl]carbamate

To a solution of tert-butyl N-(2-prop-2-ynoxyethyl)carbamate (689 mg,3.46 mmol, synthesized via Step 1 on Intermediate CP) and3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (450 mg, 1.38mmol, Intermediate JF) in DMF (10 mL) was added Pd(PPh₃)₂Cl₂ (194 mg,276 umol), CuI (52.7 mg, 277 umol) and Cs₂CO₃ (2.25 g, 6.92 mmol). Thereaction was stirred at 80° C. for 3 hrs under N₂. On completion, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give a residue. The residue was purified by reverse phase (0.1% FAcondition) to give the title compound (510 mg, 83% yield) as a brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (s, 1H), 7.31 (dd, J=7.2 Hz,1H), 7.26-7.19 (m, 2H), 6.92-6.77 (m, 1), 5.46-5.32 (m, 1), 4.45 (s,2H), 3.52 (t, J=6.0 Hz, 3H), 3.12 (q, J=5.6 Hz, 2H), 2.93-2.82 (m, 1),2.66-2.57 (m, 1), 2.22-2.13 (m, 1), 1.36 (s, 9H); LC-MS (ESI⁺) m/z 344.1(M+H−100)⁺.

Step2—Tert-butylN-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynoxy]ethyl]carbamate(340 mg, 766 umol) in THF (20 mL) was added Pd(OH)₂/C (150 mg, 10 wt %)and Pd/C (150 mg, 50 wt %). The reaction mixture was stirred at 25° C.for 2 hrs under H₂ (15 psi). On completion, the reaction mixture wasfiltered through celite and concentrated in vacuo to give the titlecompound (350 mg, 90% yield) as gray solid. LC-MS (ESI⁺) m/z 348.1(M+H−100)⁺.

Step3—3-[7-[3-(2-Aminoethoxy)propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propoxy]ethyl]carbamate (70.0 mg, 156 umol) in DCM (2 mL) was added HCl/dioxane(4 M, 1 mL). The reaction mixture was stirred at 25° C. for 2 hrs. Oncompletion, the reaction mixture was filtered and the filter cake wasconcentrated in vacuo to give the title compound (60.0 mg, 99% yield,HCl) as a white solid. LC-MS (ESI⁺) m/z 348.1 (M+H)⁺.

4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-(4-formylphenyl)pyrazole-3-carboxylicacid (Intermediate QU)

Step 1—Methyl 4-amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxylate

To a solution of methyl1-[4-(hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carboxylate (15.0 g, 54.1mmol, synthesized via Step 1 of Intermediate GB) in MeOH (200 mL) wasadded Pd/C (5.00 g, 10 wt %). The reaction mixture was stirred at 25° C.for 2 hours under H₂ (15 Psi). On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (13.0 g, 97% yield) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.82 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H),5.27 (t, J=5.6 Hz, 1H), 4.89 (s, 2H), 4.53 (d, J=5.6 Hz, 2H), 3.83 (s,3H).

Step 2—Methyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxylate

To a solution of methyl4-amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxylate (4.10 g, 16.5mmol) and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (5.14 g, 13.2 mmol, Intermediate CM) in DMF (100 mL) was addedDIPEA (4.29 g, 33.1 mmol) and HATU (6.31 g, 16.5 mmol). The reactionmixture was stirred at 25° C. for 0.5 hour. On completion, the reactionwas quenched with water (500 mL) and the reaction mixture was filtered.The filter cake was washed with water (2×100 mL), MeOH (2×10 mL) andthen dried in vacuo to give the title compound (10.0 g, 100% yield) as ayellow solid. LC-MS (ESI⁺) m/z 639.0 (M+Na)⁺.

Step 3—Methyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-(4-formylphenyl)pyrazole-3-carboxylate

To a solution of methyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxylate(7.00 g, 11.3 mmol) in THF (250 mL) was added DMP (5.78 g, 13.6 mmol).The reaction mixture was stirred at 0° C. for 1 hour. On completion, thereaction mixture was diluted with DCM (300 mL) and filtered. Thefiltrate was concentrated in vacuo to give the title compound (7.00 g,100% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s,1H), 10.05 (s, 1H), 9.15 (d, J=3.6 Hz, 1H), 8.66 (d, J=5.2 Hz, 1), 8.33(s, 1H), 8.19 (d, J=8.8 Hz, 1), 8.11-8.03 (m, 2H), 8.03-7.95 (m, 1),7.78-7.75 (m, 1), 4.91 (q, J=8.8 Hz, 2H), 1.54 (s, 9H), 1.35 (s, 3H);LC-MS (ESI⁺) m/z 637.0 (M+Na)⁺.

Step4—4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-(4-formylphenyl)pyrazole-3-carboxylic acid

To a solution of methyl4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-(4-formylphenyl)pyrazole-3-carboxylate(4.00 g, 6.51 mmol) in THF (10 mL) and H₂O (2 mL) was added LiOH (467mg, 19.5 mmol). The reaction mixture was stirred at 25° C. for 3 hours.On completion, the reaction mixture was acidified with HCl (0.5 N) topH=6 and filtered to give the title compound (3.00 g, 76% yield) as awhite solid. LC-MS (ESI⁺) m/z 601.0 (M+H)⁺.

Tert-ButylN-[4-[4-[[1-(4-formylphenyl)-3-(4-methylpiperazine-1-carbonyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate QV)

To a solution of4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-(4-formylphenyl)pyrazole-3-carboxylic acid (1.50 g, 2.50 mmol,Intermediate QU) and 1-methylpiperazine (200 mg, 2.00 mmol, CAS#109-01-3) in DMF (50 mL) was added DIPEA (968 mg, 7.49 mmol) and HATU(949 mg, 2.50 mmol). The reaction mixture was stirred at 25° C. for 1hour. On completion, the reaction mixture was quenched with water (100mL), filtered and washed with water (2×30 mL) to give the filter cake.The filter cake was then purified by reverse phase (0.1% FA) to give thetitle compound (1.00 g, 58% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.17-11.06 (m, 1H), 10.05 (s, 1H), 9.15 (s, 1H), 9.11 (s,1H), 8.66 (d, J=5.2 Hz, 1H), 8.16 (s, 3H), 8.12-8.05 (m, 2H), 7.78-7.74(m, 1H), 4.91 (q, J=8.8 Hz, 2H), 4.39-4.32 (m, 2H), 3.85-3.70 (m, 2H),2.48-2.40 (m, 4H), 2.24 (s, 3H), 1.54 (s, 9H); LC-MS (ESI⁺) m/z 683.1(M+H)⁺.

4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(4-methylpiperazine-1-carbonyl)pyrazol-1-yl]benzoicAcid (Intermediate QW)

To a solution of tert-butylN-[4-[4-[[1-(4-formylphenyl)-3-(4-methylpiperazine-1-carbonyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(100 mg, 146 umol, Intermediate QV) and NaH₂PO₄ (87.8 mg, 732 umol) inACN (1 mL) was added H₂O₂ (33.2 mg, 292 umol, 30% sol) at 0° C. Thensodium chlorite (92.7 mg, 1.03 mmol) in H₂O (1 mL) was added dropwise at0° C. The reaction mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was acidified by HCl (0.5 N) to pH=6and filtered. The filter cake was collected and dried in vacuo to givethe title compound (100 mg, 97% yield) as a white solid. LC-MS (ESI) m/z699.1 (M+H).

Tert-ButylN-[4-[4-[[3-[2-(dimethylamino)ethylcarbamoyl]-1-(4-formylphenvl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate OX)

To a solution of4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-(4-formylphenyl)pyrazole-3-carboxylicacid (800 mg, 1.33 mmol, Intermediate QU) andN′,N′-dimethylethane-1,2-diamine (117 mg, 1.33 mmol, 145 uL, CAS#108-00-9) in DMF (10 mL) was added HATU (607 mg, 1.60 mmol) and DIPEA(860 mg, 6.66 mmol, 1.16 mL). The reaction mixture was stirred at 25° C.for 2 hrs. On completion, the reaction mixture was concentrated in vacuoto give a residue. The residue was purified by reverse phase (0.1% FAcondition) to give the title compound (230 mg, 25% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 10.05 (s, 1H), 9.12(s, in), 8.70 (t, J=5.2, 1H), 8.66 (d, J=5.2 Hz, 1H), 8.29 (s, 1H),8.26-8.08 (m, 5H), 7.80-7.74 (in, in), 4.90 (q, J=8.8 Hz, 2n), 3.54-3.48(in, 2n), 2.71-2.63 (in, 2n), 2.36 (s, 6n), 1.54 (s, 9n); LC-MS (ESI⁺)m/z 671.3 (M+H)⁺.

4-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino-3-[2-(dimethylamino)ethylcarbamoyl]pyrazol-1-yl]benzoicAcid (Intermediate QY)

To a solution of tert-butylN-[4-[4-[[3-[2-(dimethylamino)ethylcarbamoyl]-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]2-yl]-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(150 mg, 223 umol, Intermediate QX) in CH₃CN (10 mL) was added asolution of NaH₂PO₄ (134 mg, 1.12 mmol and NaClO₂ (141 mg, 1.57 mmol) inH₂O (10 mL) at 0° C., then H₂O₂ (126 mg, 1.12 mmol, 107 uL, 30% sol) wasadded to the mixture. The reaction mixture was stirred at 25° C. for 3hrs. On completion, the mixture was diluted with 0.5N HCl (10 mL) andextracted with EA (2×40 mL). The organic phase was concentrated in vacuoto give the title compound (120 mg, 78% yield) as a white solid. LC-MS(ESI⁺) m/z 687.2 (M+H)⁺.

12-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-12-oxo-dodecanoicAcid (Intermediate QZ)

Step 1—Methyl12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate

To a solution of 12-methoxy-12-oxododecanoic acid (0.623 g, 2.55 mmol,CAS #3909-40-0) in DMF (20 mL) was added HATU (0.989 g, 2.55 mmol) andDIPEA (0.599 g, 4.64 mmol). The mixture was stirred for 10 min at rt.Then to the mixture was added a solution of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamideHCl salt (1 g, 2.32 mmol, Intermediate G) in DMF (10 mL) and the mixturewas stirred for 3 h at rt. On completion, H₂O (50 mL) was added to themixture, then extracted with EA (100 mL). The organic layer was washedwith brine, dried over Na₂SO₄, filtered, concentrated and purified bycolumn (PE/EA=1/1 to EA) to give the title compound (700 mg, 50% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 7.39-7.31 (m,5H), 6.10 (d, J=8.8 Hz, 1H), 4.73 (t, J=8.0 Hz, 1H), 4.61-4.48 (m, 3H),4.34 (dd, J=1.6 Hz, J=14.8 Hz, 1H), 4.15-4.10 (m, 1H), 3.66 (s, 3H),3.60 (dd, J=3.6 Hz, J=11.6 Hz, 1H), 2.56-2.53 (m, 4H), 2.29 (t, J=7.6Hz, 2H), 2.21-2.10 (m, 3H), 1.62-1.57 (m, 4H), 1.28-1.26 (m, 11H), 0.93(s, 9H). LC/MS (ESI, m/z): [M+1]⁺=657.6.

Step2—12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoicAcid

To a solution of methyl12-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-12-oxododecanoate(2.4 g, 3.65 mmol) in MeOH (30 mL), H₂O (30 mL) and THF (30 mL) wasadded NaOH (877 mg, 21.9 mmol). The mixture was stirred for 3 h at rt.To the mixture was added then added 0.06 N HCl until the pH=6.5, thenthe mixture was extracted with EA (100 mL). The organic layer was washedwith brine (50 mL), dried over Na₂SO₄, filtered, concentrated to thetitle compound (2.3 g, 100% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.89 (s, 1H), 7.39 (s, 4H), 7.20 (t, J=7.2 Hz, 1H), 7.12 (d,J=9.2 Hz, 1H), 4.74-4.64 (m, 3H), 4.58 (s, 1H), 4.33 (dd, J=4.8 Hz,J=14.8 Hz, 1H), 4.21 (d, J=11.2 Hz, 1H), 3.69 (dd, J=4.0 Hz, J=12 Hz,1H), 2.58 (s, 3H), 2.51-2.45 (m, 1H), 2.35 (t, J=6.0 Hz, 2H), 2.26-2.19(m, 3H), 1.69-1.56 (m, 4H), 1.34-1.28 (m, 12H), 0.95 (s, 9H). LC/MS(ESI, m/z): [M+1]⁺=643.3.

2-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid (Intermediate RA)

Step1—(S)-19-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-20,20-dimethyl-17-oxo-3,6,9,12,15-pentaoxa-18-azahenicosanoicAcid

To a mixture of 3,6,9,12,15-pentaoxaheptadecanedioic acid (1.04 g, 3.36mmol, Intermediate UF), DIPEA (289 mg, 2.24 mmol) in DMF (15 mL) wasadded HATU (511 mg, 1.344 mmol). Then the(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride (500 mg, 1.12 mmol, Intermediate G) in DMF (5 mL) wasadded dropwise to the solution. After the addition, the mixture wasstirred at rt for 30 min. Then the mixture was poured into water,acidified to pH<6 by addition of 1M HCl, then extracted with EtOAc (3×30mL). The combined organic layers was washed with brine (50 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by prep HPLC to give the title compound (311 mg, 38% yield)as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 9.05 (s, 1H),7.53-7.44 (m, 4H), 4.74-4.70 (m, 1H), 4.61-4.51 (m, 3H), 4.38 (d,J=15.51 Hz, 1H), 4.13 (s, 2H), 4.08 (d, J=3.13 Hz, 2H), 3.90-3.81 (m,2H), 3.73-3.63 (m, 16H), 2.52 (s, 3H), 2.27-2.08 (m, 2H), 1.07 (s, 9H);LC/MS (ESI, m/z): [M+1]⁺=723.2.

2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]aceticAcid Intermediate RB)

Step1—(S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanoicAcid

To a mixture of 2,2′-((oxybis(ethane-2,1-diyl))bis(oxy))diacetic acid(1.36 g, 4.3 mmol, CAS #13887-98-4), DIPEA (415 mg, 3.23 mmol) in DMF (5mL) was added HATU (488 mg, 1.29 mmol). Then(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride (500 mg, 1.12 mmol, Intermediate G) in DMF (5 mL) wasadded dropwise into the mixture. After the addition, the mixture wasstirred at rt for 30 min. Then the mixture was poured into water,acidified to pH<6 by the addition of 1M HCl, then extracted with EtOAc(3×30 mL). The combined organic layers was washed with brine (50 mL×2),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by prep HPLC to give the title compound (125 mg,18%) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 9.10 (br. s.,1H), 7.45-7.25 (m, 4H), 4.60 (s, 1H), 4.50-4.40 (m, 3H), 4.26 (d,J=15.51 Hz, 1H), 4.03-3.94 (m, 4H), 3.79-3.68 (m, 2H), 3.63-3.58 (m,8H), 2.41 (s, 3H), 2.16-1.93 (m, 2H), 0.94 (s, 9H); LC/MS (ESI, m/z):[M+1]⁺=635.1.

5-(4-Tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicAcid (Intermediate RC)

Step 1—Ethyl5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

To a mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate(0.50 g, 2.22 mmol, CAS #1224944-77-7) and tert-butylpiperazine-1-carboxylate (619 mg, 3.32 mmol) in MeCN (6 mL) was addedDIPEA (857 mg, 6.63 mmol, 1.16 mL), and the resulting mixture wasstirred at 60° C. for 2 hours. On completion, the mixture wasconcentrated in vacuo. The residue was diluted with water (30 mL) andacidified with HCl (1 N) until the pH=5, then the mixture was extractedwith EA (3×50 mL). The combined organic layers was dried over Na₂SO₄,filtered and concentrated in vacuo to give the compound (0.81 g, 97%yield) as white solid; ¹H NMR (400 MHz, CDCl₃) δ 8.32-8.31 (m, 1H), 8.29(s, 1H), 6.43-6.41 (m, 1H), 4.38-4.32 (m, 2H), 3.90-3.80 (m, 4H),3.59-3.56 (m, 4H), 1.49 (s, 9H), 1.41-1.37 (m, 3H).

Step2—5-(4-Tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicAcid

To a solution of ethyl5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.80 g, 2.13 mmol) in THF (16.0 mL) was addeda solution of LiOH H₂O (223 mg, 5.33 mmol) in H₂O (4.00 mL). Thereaction mixture was stirred at 20° C. for 16 hours, then an additionalsolution of LiOH H₂O (1.00 g, 23.8 mmol) in H₂O (4.00 mL) was added, andthe reaction mixture was stirred at 20° C. for 8 hours. The mixture wasthen heated to 45° C. and stirred for 16 hours. On completion, themixture was concentrated in vacuo. The residue was extracted with EA (20mL) to remove organic impurities. Then the water phase was acidifiedwith 1 N HCl (aq.) until pH=4, and extracted with EA/MeOH (10/1, 2×20mL). The combined organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (0.72 g, 97% yield) asyellowish solid. ¹H NMR (400 MHz, CDCl₃) δ 8.74-8.72 (m, 1H), 8.17 (s,1), 6.84-6.82 (m, 1), 3.75-3.74 (m, 4H), 3.46-3.43 (m, 4H), 1.42 (s,9H).

N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide(Intermediate RD)

Step 1—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate

To a mixture of 3-(difluoromethyl)-1-methyl-pyrazol-4-amine (847 mg,5.76 mmol, Intermediate LU),5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (2.00 g, 5.76 mmol, Intermediate RC) in DMF (20 mL) was added DIPEA(2.23 g, 17.3 mmol) and HATU (2.63 g, 6.91 mmol). The reaction mixturewas stirred at 20° C. for 1 hour. On completion, the reaction mixturewas poured into water (60 mL). The aqueous phase was extracted withethyl acetate (2×30 mL). The combined organic phase was washed withbrine (2×30 mL), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by column chromatography (SiO₂, Ethylacetate) to give the title compound (734 mg, 26% yield) as reddish brownsolid. ¹H NMR (400 MHz, CDCl₃) δ 9.42 (s, 1H), 8.37 (s, 1H), 8.32-8.25(m, 2H), 6.70 (t, J=54.0 Hz, 1H), 6.35 (d, J=8.0 Hz, 1H), 3.83 (s, 3H),3.75 (s, 4H), 3.59-3.49 (m, 4H), 1.44 (s, 9H).

Step2—N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of tert-butyl4-[3-[[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (684 mg, 1.44 mmol) in DCM (2mL) was added HCl/dioxane (4 M, 717 uL). The reaction mixture wasstirred at 25° C. for 1 hour. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (575 mg, 91% yield,HCl) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.65 (s, 2H), 9.33(s, 1H), 8.90 (d, J=8.0 Hz, 1H), 8.35 (d, J=12.4 Hz, 1H), 7.13 (t,J=53.6 Hz, 1H), 6.96 (d, J=7.6 Hz, 1H), 4.08 (s, 4H), 3.89 (s, 3H), 3.23(s, 4H). LC-MS (ESI⁺) m/z 377.2 (M+H)⁺.

3-[5-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate RG)

Step 1—Tert-ButylN-[2-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-zyl]ethoxy]ethyl]carbamate

To a mixture of3-(3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione(20.0 mg, 582 umol, Intermediate PN) in THF (4 mL) and DMF (4 mL) wasadded TEA (589 mg, 5.82 mmol, 811 uL). The reaction mixture was stirredat 25° C. for 0.5 hour. Then tert-butyl N-[2-(2-oxoethoxy)ethyl]carbamate (500 mg, 2.46 mmol, synthesized via Step 1 ofIntermediate FS) and HOAc (385 mg, 6.41 mmol, 366 uL) were added to theabove solution. The reaction mixture was stirred at 25° C. for 0.5 hour.Then NaBH(OAc)₃ (247 mg, 1.16 mmol) was added to the reaction mixture.Then the mixture was stirred at 25° C. for 6 hrs under N₂ atmosphere. Oncompletion, the mixture was concentrated in vacuo give a residue. Theresidue was purified by reversed-phase HPLC (0.1% FA condition) to givethe title compound (60.0 mg, 19% yield) as a yellow solid. LC-MS (ESI⁺)m/z 531.3 (M+H)⁺.

Step2—3-[5-[4-[2-(2-Aminoethoxy)ethyl]piperazin-1-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]ethoxy]ethyl]carbamate (60.0 mg, 113 umol) in DCM (10 mL)was added TFA (4.62 g, 40.5 mmol, 3.00 mL). The mixture was stirred at15° C. for 0.5 hr. On completion, the mixture was concentrated in vacuoto give the title compound (50.0 mg, 95% yield) as yellow oil. LC-MS(ESI⁺) m/z 431.2 (M+H)⁺.

3-[5-[3-(2-Aminoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate RH)

Step 1—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethyl]carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg, 1.77 mmol, Intermediate HN) and tert-butylN-(2-prop-2-ynoxyethyl)carbamate (883 mg, 4.44 mmol, synthesized viaStep 1 on Intermediate CP) in DMF (10 mL) was added Cs₂CO₃ (2.31 g, 7.10mmol), CuI (67.5 mg, 354 umol), 4Å molecular sieve (20 mg) andPd(PPh₃)₂Cl₂ (249 mg, 354. umol). The mixture was heated at 80° C. for 2hours. On completion, the reaction mixture was filtered and the filtratewas concentrated in vacuo. The residue was diluted with water (30 mL),and then extracted with EA (3×40 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by prep-HPLC (FA condition) to give the titlecompound (650 mg, 80% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.12 (s, 1H), 7.32 (s, 1H), 7.19-7.10 (m, 2H), 6.90-6.78 (m,1H), 5.39 (dd, J=5.6, 12.8 Hz, 1H), 4.37 (s, 2H), 4.11 (d, J=2.4 Hz,1H), 3.50 (t, J=6.0 Hz, 2H), 3.34 (s, 3H), 3.18-3.09 (m, 2H), 2.95-2.82(m, 1H), 2.73-2.55 (m, 2H), 2.09-1.99 (m, 1H), 1.37 (s, 9H); LC-MS(ESI⁺) m/z 357.2 (M+H−100)⁺.

Step 2—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethyl]carbamate (600 mg, 1.31 mmol) in THF (20 mL) wasadded Pd(OH)₂/C (150 mg, 10 wt %) and Pd/C (150 mg, 10 wt %) under N₂.The suspension was degassed under vacuum and purged with H₂ gas threetimes. The mixture was stirred at 25° C. for 16 hours under H₂ (15 PSI).On completion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (500 mg, 82% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.08-6.92 (m,2H), 6.86 (dd, J=1.2, 8.4 Hz, 1), 6.77 (t, J=5.2 Hz, 1H), 5.33 (dd,J=5.2, 12.8 Hz, 1H), 3.39-3.33 (m, 4H), 3.32 (s, 3H), 3.15-3.03 (m, 2H),2.97-2.81 (m, 1H), 2.73-2.58 (m, 4H), 2.03-1.95 (m, 1H), 1.86-1.74 (m,2H), 1.37 (s, 9H); LC-MS (ESI⁺) m/z 483.1 (M+Na)⁺.

Step3—3-[5-[3-(2-Aminoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl]carbamate (150 mg, 325 umol) in DCM (3 mL) was added TFA(1.54 g, 13.5 mmol). The mixture was stirred at 30° C. for 0.5 hour. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (150 mg, 97% yield, TFA) as light yellow solid. LC-MS(ESI⁺) m/z 361.1 (M+H)⁺.

4-3-[4-[3-(2-Aminoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate RI)

Step 1—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethyl]carbamate

To a mixture of tert-butyl N-(2-prop-2-ynoxyethyl)carbamate (4.42 g,22.1 mmol, synthesized via Step 1 on Intermediate CP) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (3.00g, 8.87 mmol, Intermediate HP) in DMF (50 mL) was added Cs₂CO₃ (14.4 g,44.3 mmol), CuI (168 mg, 887 umol) and Pd(PPh₃)₂Cl₂ (622 mg, 887 umol).The reaction mixture was stirred at 80° C. for 2 hours. On completion,the reaction mixture was filtered and concentrated in vacuo. The residuewas diluted with water (50 mL) and extracted with EA (3×100 mL). Thecombined organic layers was dried over Na₂SO₄, filtered and concentratedin vacuo to give a residue. The residue was purified by prep-HPLC (0.1%FA condition) to give the title compound (2.70 g, 66% yield) as brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.23-7.09 (m, 2H),7.08-6.99 (m, 1H), 6.92-6.82 (m, 1H), 5.45-5.36 (m, 1H), 4.44 (s, 2H),3.64 (s, 3H), 3.52 (t, J=6.0 Hz, 2H), 3.16-3.08 (m, 2H), 2.96-2.83 (m,1H), 2.78-2.60 (m, 2H), 2.07-1.95 (m, 1H), 1.36 (s, 9H).

Step 2—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethyl]carbamate(200 mg, 438 umol) in THF (5 mL) was added Pd/C (100 mg, 10 wt %) andPd(OH)₂/C (100 mg, 10 wt %). The reaction mixture was stirred at 25° C.for 12 hours under H₂ (15 PSI) atmosphere. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (200 mg, 99% yield) as light yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 7.00-6.92 (m, 2H), 6.91-6.84 (m, 1H), 6.79 (s,1H), 5.39-5.32 (m, 1H), 3.56 (s, 3H), 3.44 (t, J=6.0 Hz, 2H), 3.40-3.38(m, 2H), 3.09 (d, J=5.6 Hz, 2H), 2.98-2.93 (m, 2H), 2.90-2.83 (m, 1H),2.71-2.60 (m, 2H), 2.03-1.94 (m, 1H), 1.88-1.76 (m, 2H), 1.37 (s, 9H).

Step3—4-3-[4-[3-(2-Aminoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethyl]carbamate (200 mg, 434 umol) in DCM (3 mL) was addedHCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25° C. for1 hour. On completion, the reaction mixture was concentrated in vacuo togive the title compound (172 mg, 99% yield) as light yellow solid. LC-MS(ESI⁺) m/z 361.1 (M+H)⁺.

3-[5-[3-[(2R)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate RJ)

Step 1—Tert-Butyl N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate

To a solution of tert-butyl N-[[(2S)-morpholin-2-yl]methyl]carbamate(1.00 g, 4.62 mmol, CAS #875551-59-0) and 3-bromoprop-1-yne (550 mg,4.62 mmol) in THF (20 mL) was added K₂CO₃ (1.28 g, 9.25 mmol). Thereaction mixture was stirred at 25° C. for 12 hours. On completion, themixture was diluted with water (30 mL) and extracted with EA (3×80 mL).The combined organic layers was dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/1 to 2/1)to give the title compound (800 mg, 68% yield) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 4.93 (s, 1H), 3.93-3.87 (m, 1H), 3.68 (dt, J=2.4,11.2 Hz, 1H), 3.64-3.57 (m, 1H), 3.31 (d, J=2.4 Hz, 2H), 3.15-3.05 (m,1H), 2.78-2.72 (m, 1H), 2.70-2.65 (1H), 2.39 (dt, J=3.6, 11.2 Hz, 1H),2.27 (t, J=2.4 Hz, 1H), 2.13 (t, J=10.8 Hz, 1H), 1.87 (s, 1H), 1.45 (s,9H).

Step 2—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (846 mg, 3.33mmol) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (450mg, 1.33mmol, Intermediate HN) in DMF (15 mL) was added Cs₂CO₃ (2.17 g,6.65 mmol), CuI (25.3 mg, 133 umol) and Pd(PPh₃)₂Cl₂ (93.4 mg, 133umol). The reaction mixture was stirred at 80° C. for 2 hr under N₂. Oncompletion, the mixture was filtered, and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (550 mg, 80% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.28 (s, 1H),7.16-7.10 (m, 2H), 6.86-6.83 (m, 1H), 5.38 (dd, J=5.2, 12.4 Hz, 1H),3.79 (t, J=13.2 Hz, 2H), 3.52 (s, 2H), 3.34 (s, 3H), 3.01-2.92 (m, 3H),2.80-2.70 (m, 2H), 2.69-2.65 (m, 2H), 2.35-2.27 (m, 1H), 2.25-2.15 (m,1H), 2.06-1.95 (m, 2H), 1.37 (s, 9H); LC-MS (ESI⁺) m/z 512.2 (M+H)⁺.

Step 3—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate (300 mg, 586 umol) in THF(10 mL) was added Pd/C (100 mg, 10 wt %) and Pd(OH)₂/C (100 mg, 10 wt%). The reaction mixture was stirred at 25° C. under H₂ (15 psi) for 12hours. On completion, the residue was filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 1%-31%, 10 min) to give the title compound(120 mg, 39% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08(s, 1H), 7.04 (s, 1), 7.00 (d, J=8.0 Hz, 1), 6.87 (d, J=8.0 Hz, 1), 6.82(t, J=5.6 Hz, 1), 5.33 (dd, J=5.2, 12.8 Hz, 1H), 3.43-3.40 (m, 3H), 3.32(s, 3H), 3.03-2.87 (m, 3H), 2.73-2.58 (m, 6H), 2.36-2.25 (m, 2H),2.03-1.95 (m, 2H), 1.79-1.66 (m, 3H), 1.36 (s, 9H); LC-MS (ESI⁺) m/z516.3 (M+H)⁺.

Step4—3-[5-[3-[(2R)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]carbamate (120 mg, 232 umol) in DCM (3 mL)was added HCl/dioxane (4 M, 1 mL). The reaction mixture was stirred at25° C. for 2 hours. On completion, the mixture was concentrated in vacuoto give the title compound (100 mg, 95% yield) as a white solid. LC-MS(ESI⁺) m/z 416.2 (M+H)⁺.

3-[5-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate RK)

Step 1—Tert-Butyl N-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate

To a mixture of tert-butyl N-[[(2R)-morpholin-2-yl]methyl]carbamate (3g, 13.8 mmol, CAS #186202-57-3) and 3-bromoprop-1-yne (1.98 g, 16.6mmol) in THF (60 mL) was added K₂CO₃ (3.83 g, 27.7 mmol). The reactionmixture was stirred at 25° C. for 16 hours. On completion, the reactionmixture was filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=4/1) to give the title compound (2.4 g, 68% yield)as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.90 (s, 1H), 3.96-3.83(m, 1H), 3.74-3.50 (m, 2H), 3.33-3.25 (m, 3H), 3.13-3.08 (m, 1H),2.78-2.62 (m, 2H), 2.41-2.33 (m, 1H), 2.26 (t, J=2.4 Hz, 1H), 2.13 (t,J=10.4 Hz, 1H), 1.44 (s, 9H).

Step 2—Tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (265mg, 784 umol, Intermediate HN) and tert-butylN-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (299 mg, 1.18mmol) in DMF (15 mL) was added CuI (29.9 mg, 157 umol), Pd(PPh₃)₂Cl₂(110 mg, 157 umol), Cs₂CO₃ (1.02 g, 3.13 mmol) and 4Å molecular sieves(20 mg) at 25° C. The reaction mixture was stirred at 80° C. for 3hours. On completion, the reaction mixture was filtered and the filtratewas concentrated in vacuo to give a residue. The residue was dilutedwith water (30 mL), and then extracted with EA (3×50 mL). The combinedorganic layers were washed with brine (50 mL), then dried over Na₂SO₄,filtered and the filtrate was concentrated in vacuo to give a residue.The residue was purified by reverse phase (0.1% FA condition) to givethe title compound (270 mg, 67% yield) as a white solid. 1H NMR (400MHz, CDCl₃) δ 8.18 (s, 1H), 7.17 (d, J=1.2 Hz, 1H), 7.10 (s, 1H), 6.73(d, J=8.4 Hz, 1H), 5.20-5.16 (m, 1H), 4.93-4.89 (in, 1H), 3.95-3.89 (in,1H), 3.72-3.71 (m, 1H), 3.54-3.49 (m, 2H), 3.43 (s, 3H), 3.15-3.07 (m,1H), 2.99-2.99 (m, 1H), 2.99-2.92 (m, 1H), 2.89-2.61 (m, 6H), 2.48-2.40(m, 1), 2.28-2.22 (m, 1), 2.17 (t, J=3.6 Hz, 1), 1.43 (s, 9H); LC-MS(ESI⁺) m/z 512.3 (M+H)⁺.

Step 3—Tert-ButylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate(270 mg, 528 umol) in THF (15 mL) was added Pd/C (120 mg, 528 umol, 10wt %) and Pd(OH)₂/C (110 mg, 528 umol, 10 wt %) at 25° C. The reactionmixture was stirred at 25° C. for 2 hours under H₂ (15 PSI). Oncompletion, the reaction mixture was filtered with celite and thefiltrate was concentrated in vacuo to give a residue. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(230 mg, 85% yield) as a brown solid. LC-MS (ESI⁺) m/z 516.1 (M+H)⁺.

Step4—3-[5-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]carbamate (130 mg, 252 umol) in DCM (2 mL)was added TFA (1.67 g, 14.6 mmol). The reaction mixture was stirred at25° C. for 2 hours. On completion, the reaction mixture was concentratedin vacuo to give the title compound (100 mg, 95% yield, TFA) as a brownoil. LC-MS (ESI⁺) m/z 416.3 (M+H)⁺.

2-[(2S)-4-prop-2-ynylmorpholin-2-yl]acetonitrile (Intermediate RL)

Step 1—Tert-Butyl(2R)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate

To a solution of tert-butyl(2R)-2-(hydroxymethyl)morpholine-4-carboxylate (10.0 g, 46.0 mmol, CAS#135065-71-3) and TEA (9.32 g, 92.0 mmol) in DCM (100 mL) was added MsCl(6.36 g, 55.5 mmol) at 0° C. The reaction mixture was stirred at 25° C.for 2 hours. On completion, the reaction mixture was poured intosat.NaHCO₃ (50 mL) and extracted with EA (3×300 mL). The combinedorganic layers were washed with brine (300 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(13.5 g, 99% yield) as colorless oil, ¹H NMR (400 MHz, CDCl₃) δ 4.23 (d,J=4.8 Hz, 2H), 4.06-3.77 (m, 3H), 3.74-3.64 (m, 1H), 3.59-3.49 (m, 1H),3.06 (s, 3H), 3.01-2.88 (m, 1H), 2.81-2.67 (m, 1), 1.49-1.42 (m, 9H).

Step 2—Tert-Butyl (2S)-2-(cyanomethyl)morpholine-4-carboxylate

To a solution of tert-butyl(2R)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (13.0 g, 44.0mmol) and KI (10.9 g, 66.0 mmol) in DMSO (200 mL) was added KCN (3.15 g,48.4 mmol, 2.07 mL). The reaction mixture was stirred at 80° C. for 3hours. The reaction mixture was then stirred at 100° C. for 4 hours. Oncompletion, the reaction mixture was poured into sat.NaHCO₃ (100 mL) andextracted with EA (3×500 mL). The combined organic layers were washedwith brine (50 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by silica columnchromatography (PE/EA=10/1 to 6/1) to give the title compound (8.00 g,80% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.10-3.78 (m,3H), 3.72-3.62 (m, 1H), 3.60-3.50 (m, 1H), 2.97 (t, J=11.2 Hz, 1H),2.84-2.65 (s, 1H), 2.62-2.50 (m, 2H), 1.47 (s, 9H).

Step 3—2-[(2S)-Morpholin-2-yl]acetonitrile

To a solution of tert-butyl (2S)-2-(cyanomethyl)morpholine-4-carboxylate(4.50 g, 19.8 mmol) in DCM (10 mL) was added TFA (138 g, 1.22 mol). Thereaction mixture was stirred at 25° C. for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give the title compound(4.70 g, 98% yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ9.29-8.83 (m, 2H), 4.05-3.88 (m, 2H), 3.77-3.63 (m, 1H), 3.31-3.15 (m,2H), 3.03-2.76 (m, 3H), 2.41-2.18 (m, 1H).

Step 4—2-[(2S)-4-prop-2-ynylmorpholin-2-yl]acetonitrile

To a solution of 2-[(2S)-morpholin-2-yl]acetonitrile (4.70 g, 19.5 mmol,TFA) and 3-bromoprop-1-yne (3.49 g, 29.3 mmol) in THF (100 mL) was addedKI (324 mg, 1.96 mmol) and K₂CO₃ (8.11 g, 58.7 mmol). The reactionmixture was stirred at 25° C. for 48 hours. On completion, the reactionmixture was diluted with EA (500 mL) and filtered to give the filtrate.The filtrate was concentrated in vacuo to give a residue. The residuewas purified by silica column chromatography (PE/EA=10/1 to 6/1) to givethe title compound (1.50 g, 46% yield) as a light yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 3.97-3.90 (m, 1H), 3.87-3.78 (m, 1H), 3.70 (dt,J=2.4, 11.2 Hz, 1H), 3.33 (d, J=2.0 Hz, 2H), 2.85-2.80 (m, 1H),2.67-2.60 (m, 1H), 2.56 (d, J=6.0 Hz, 2H), 2.44 (dt, J=3.2, 11.2 Hz, 1),2.29 (t, J=2.4 Hz, 1H), 2.35 (t, J=10.0 Hz, 1H).

3-[5-[3-[(2S)-2-(2-aminoethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate RM)

Step1—2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]acetonitrile

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00g, 2.96 mmol, Intermediate HN) and2-[(2S)-4-prop-2-ynylmorpholin-2-yl]acetonitrile (971 mg, 5.91 mmol,Intermediate RL) in DMSO (50 mL) was added Pd(PPh₃)₂Cl₂ (415 mg, 591umol), DIPEA (1.91 g, 14.7 mmol) and CuI (112 mg, 591 umol). Thereaction mixture was stirred at 85° C. for 2 hours. On completion, thereaction mixture was filtered. The filtrate was diluted with EA (30 mL),poured into water (300 mL) and extracted with EA (2×200 mL). The organiclayer was washed with water (2×200 mL), brine (200 mL), dried withanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo.The residue was purified by reversed-phase chromatography (FA, 0.1%) togive the title compound (1.00 g, 80% yield) as a yellow solid. LC-MS(ESI⁺) m/z 422.2 (M+H)⁺.

Step2—3-[5-[3-[(2S)-2-(2-aminoethyl)morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]acetonitrile(600 mg, 1.42 mmol) and AcOH (170 mg, 2.85 mmol) in THF (40 mL) wasadded Raney-Ni (50.0 mg, 583 umol). The reaction mixture was stirred at25° C. for 4 hours under H₂ (50 Psi). On completion, the reactionmixture was filtered. The filter cake was triturated with water (3×30mL) and filtered to give the filtrate. The filtrate was concentrated invacuo to give the title compound (600 mg, 100% yield, HOAc) as lightyellow oil. LC-MS (ESI⁺) m/z 426.1 (M+H)⁺.

Step3—3-[5-[3-[(2S)-2-(2-aminoethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-[5-[3-[(2S)-2-(2-aminoethyl)morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(550 mg, 1.13 mmol, HOAc) in THF (30 mL) was added PtO₂ (51.4 mg, 226umol). The reaction was stirred at 25° C. for 4 hours under H₂ (15 Psi).On completion, the reaction mixture was filtered to give the filtrateand concentrated in vacuo to give the title compound (400 mg, 100%yield, HOAc) as yellow oil. LC-MS (ESI⁺) m/z 430.2 (M+H)⁺.

2-[(2R)-4-Prop-2-ynylmorpholin-2-yl]acetonitrile (Intermediate RN)

Step 1—Tert-Butyl(2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate

To a mixture of tert-butyl(2S)-2-(hydroxymethyl)morpholine-4-carboxylate (5.00 g, 23.0 mmol, CAS#135065-76-8) in DCM (50 mL) was added TEA (3.03 g, 29.9 mmol) and MsCl(6.06 g, 52.9 mmol) at 0° C. Then the reaction mixture was stirred at25° C. for 2 hours. On completion, the reaction mixture was poured intothe ice-water (50 mL), and extracted with DCM (2×30 mL). The combinedorganic phase was washed with brine (2×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(6.50 g, 95% yield) as a white oil. ¹H NMR (400 MHz, CDCl₃) δ 4.23 (d,J=4.8 Hz, 2H), 3.92-3.85 (m, 3H), 3.69-3.65 (m, 1H), 3.57-3.51 (m, 1H),3.06 (s, 3H), 3.01-2.95 (m, 1H), 2.82-2.76 (m, 1H), 1.46 (s, 9H).

Step 2—Tert-Butyl (2R)-2-(cyanomethyl)morpholine-4-carboxylate

To a mixture of tert-butyl(2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (6.50 g, 22.0mmol) in DMSO (80 mL) was added KCN (1.50 g, 23.1 mmol) and KI (5.48 g,33.0 mmol) at 25° C. The reaction mixture was then stirred at 100° C.for 4 hours. On completion, the reaction mixture was poured into theice-water (50 mL), and extracted with DCM (2×30 mL). The combinedorganic phase was washed with brine (2×50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography (SiO₂, petroleumether/ethyl acetate=3:1) to give the title compound (2.30 g, 46% yield)as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 4.04-3.83 (m, 3H), 3.62-3.59(m, 1H), 3.51-3.48 (m, 1H), 2.93-2.90 (m, 1H), 2.68 (m, 1H), 2.50-2.43(m, 2H), 1.40 (s, 9H).

Step 3—2-[(2R)-Morpholin-2-yl]acetonitrile

To a solution of tert-butyl (2R)-2-(cyanomethyl)morpholine-4-carboxylate (1.00 g, 4.42 mmol) in DCM (6 mL) was added TFA(3 mL) at 25° C. The mixture was stirred at 25° C. for 1 hour. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (1.06 g, 95% yield, TFA) as light yellow gum. ¹H NMR (400 MHz,DMSO-d₆) δ 9.11 (s, 2H), 4.04-4.01 (m, 1H), 4.00-3.91 (m, 1H), 3.79-3.67(m, 1H), 3.34-3.16 (m, 2H), 3.07-2.89 (m, 2H), 2.87-2.73 (m, 2H).

Step 4—2-[(2R)-4-Prop-2-ynylmorpholin-2-yl]acetonitrile

To a mixture of 2-[(2R)-morpholin-2-yl]acetonitrile (1.06 g, 4.41 mmol,TFA) and K₂CO₃ (1.83 g, 13.2 mmol) in DMF (15 mL) was added3-bromoprop-1-yne (577 mg, 4.85 mmol) at 25° C. The mixture was stirredat 25° C. for 16 hours. On completion, the mixture was filtered and thecake was washed with EA (20 mL). The filtrate and washing were combinedand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, PE:EA=20:1-5:1) to give the title compound (650mg, 89% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.93 (m,1H), 3.88-3.81 (m, 1H), 3.72 (m, 1H), 3.36-3.30 (m, 2H), 2.88 (s, 1H),2.68 (m, 1H), 2.57 (d, J=6.0 Hz, 2H), 2.46 (m, 1H), 2.32-2.21 (m, 2H).

3-[5-[3-[(2R)-2-(2-Aminoethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate RO)

Step1—2-[(2R)-4-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]acetonitrile

A mixture of 2-[(2R)-4-prop-2-ynylmorpholin-2-yl]acetonitrile (588 mg,3.58 mmol, Intermediate RN),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (480mg, 1.42 mmol, Intermediate HN), CuI (58 mg, 304 umol), Pd(PPh₃)₂Cl₂(201 mg, 286 umol), 4Å MS (300 mg) and Cs₂CO₃ (2.31 g, 7.10 mmol) in DMF(15 mL) was stirred at 80° C. for 2 hours under N₂. On completion, themixture was filtered and the filter cake was washed with EA (10 mL). Thefiltrate and washing were combined and concentrated in vacuo. Theresidue was purified by reversed phase (FA condition) and prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.1%TFA)-ACN]; B %: 2%-30%, 10 min) to give the title compound (280 mg, 47%yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.35(d, J=1.2 Hz, 1H), 7.27-7.20 (m, 1H), 7.20-7.13 (m, 1H), 5.42-5.38 (m,1H), 4.17 (s, 2H), 4.08 (d, J=12.4 Hz, 1H), 3.91 m, 1H), 3.77-3.67 (m,1H), 3.35 (s, 3H), 3.34-3.31 (m, 1H), 3.02-2.81 (m, 5H), 2.77-2.58 (m,3H), 2.06-1.97 (m, 1H).

Step2—3-[5-[3-[(2R)-2-(2-Aminoethyl)morpholin-4-yl]prop-1-enyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of2-[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]acetonitrile(270 mg, 640 umol), Raney-Ni (100 mg) and HOAc (210 mg, 3.50 mmol) inTHF (6 mL) was stirred at 25° C. for 16 hours under H₂ (45 Psi). Oncompletion, the mixture was filtered and the cake was washed with THF(10 mL). The combined organic layer was concentrated in vacuo to givethe title compound (320 mg, 100% yield, HOAc) as light yellow gum. LC-MS(ESI⁺) m/z 428.3 (M+H)⁺.

Step3—3-[5-[3-[(2R)-2-(2-Aminoethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

A mixture of 3-[5-[3-[(2R)-2-(2-aminoethyl) morpholin-4-yl]prop-1-enyl]-3-methyl-2-oxo-benzimidazol-1-yl] piperidine-2,6-dione (320mg, 640 umol) and PtO₂ (50.0 mg, 220 umol) in THF (10 mL) was stirred at25° C. for 3 hours under H₂ (15 Psi). On completion, the mixture wasfiltered and the filter cake was washed with THF (10 mL). The filtrateand washing were combined and concentrated in vacuo to give the titlecompound (280 mg, 98% yield, HOAc) as light yellow gum. LC-MS (ESI⁺) m/z430.3 (M+H)⁺.

4-[3-(Difluoromethyl)-4-[[2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]pyrazol-1-yl]benzoicAcid (Intermediate RP)

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicacid (70.0 mg, 112 umol, Intermediate JE) in DCM (4 mL) was added TFA (4mL). The reaction mixture was stirred at 25° C. for 2 hrs. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (71.5 mg, 100% yield, TFA) as a white solid. LC-MS (ESI⁺) m/z523.2 (M+H)⁺.

1-(4-methoxyphenyl)-N-methyl-N-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]methanamine(Intermediate RO)

Step 1—Tert-Butyl (2R)-2-formylmorpholine-4-carboxylate

To a solution of tert-butyl(2R)-2-(hydroxymethyl)morpholine-4-carboxylate (2.00 g, 9.21 mmol, CAS#135065-71-3) in DCM (40 mL) was added DMP (4.69 g, 11.0 mmol) at 0° C.The reaction mixture was stirred at 25° C. for 2 hours. On completion,the mixture was quenched with aq. Na₂S₂O₃ (50 mL) and aq. NaHCO₃ (50mL). The mixture was stirred for 15 minutes and extracted with EA (2×50mL). The organic layer was washed with brine (50 mL), dried with Na₂SO₄,and concentrated in vacuo to give the title compound (1.50 g, 76% yield)as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 4.08-4.00 (m,1H), 3.95-3.85 (m, 2H), 3.83-3.75 (m, 1H), 3.68-3.53 (m, 2H), 3.12-3.03(m, 1H), 1.47 (s, 9H).

Step 2—Tert-butyl(2S)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methy]morpholine-4-carboxylate

To a solution of tert-butyl (2R)-2-formylmorpholine-4-carboxylate (1.5g, 6.97 mmol) and 1-(4-methoxyphenyl)-N-methyl-methanamine (1.05 g, 6.97mmol) in DCM (30 mL) was added HOAc (418 mg, 6.97 mmol) and the reactionwas stirred at 25° C. Thirty minutes later, NaBH(OAc)₃ (1.77 g, 8.36mmol) was added and the reaction mixture was stirred at 25° C. for 10hours. On completion, the mixture was concentrated in vacuo. The residuewas purified by reversed phase (0.1% FA) to give the title compound (1.4g, 57% yield) as a yellow solid. ¹H NMR (300 MHz, CDCl₃) δ 7.22 (d,J=8.4 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 4.07-3.94 (m, 1H), 3.93-3.83 (m,2H), 3.90 (s, 3H), 3.58-3.43 (m, 4H), 3.01-2.80 (m, 1H), 2.62-2.46 (m,2H), 2.41-2.31 (m, 1H), 2.26 (s, 3H), 1.48 (s, 9H); LC-MS (ESI⁺) m/z351.1 (M+H)⁺.

Step3—1-(4-Methoxyphenyl)-N-methyl-N-[[(2R)-morpholin-2-yl]methyl]methanamineHydrochloride

To a solution of tert-butyl(2S)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholine-4-carboxylate(1.40 g, 3.99 mmol) in HCl/dioxane (10 mL) was added DCM (10 mL). Thereaction mixture was stirred at 25° C. for 2 hours. On completion, themixture was concentrated in vacuo to give the title compound (1.15 g,100% yield, HC) as a yellow solid. LC-MS (ESI⁺) m/z 251.1 (M+H)⁺.

Step4—1-(4-methoxyphenyl)-N-methyl-N-[[(2S)-4-prop-2-vnylmorpholin-2-yl]methyl]methanamine

To a solution of1-(4-methoxyphenyl)-N-methyl-N-[[(2R)-morpholin-2-yl]methyl]methanamine(1.15 g, 4.01 mmol, HCl) and 3-bromoprop-1-yne (525 mg, 4.41 mmol) inDMF (20 mL) was added K₂CO₃ (1.66 g, 12.0 mmol). The reaction mixturewas stirred at 25° C. for 12 hours. On completion, the mixture wasdiluted with water (100 mL), and extracted with EA (2×50 mL). Theorganic layer was washed with brine (100 mL), then concentrated invacuo. The residue was purified by reversed phase chromatography (0.1%FA condition) to give the title compound (700 mg, 61% yield) ascolourless oil. LC-MS (ESI⁺) m/z 289.2 (M+H)⁺.

3-[3-Methyl-5-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate RR)

Step1—3-[5-[3-[(2S)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

1-(4-methoxyphenyl)-N-methyl-N-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]methanamine(1.01 g, 3.51 mmol, Intermediate RQ),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (660mg, 1.95 mmol, Intermediate HN), Pd(PPh₃)₂Cl₂ (274 mg, 390 umol), CuI(74.3 mg, 390 umol), 4Å molecular sieves (200 mg) and Cs₂CO₃ (2.54 g,7.81 mmol) in DMF (12 mL) was degassed with N₂ and then heated at 80° C.for 2 hours under N₂. On completion, the mixture was filtered and thefiltrate was concentrated in vacuo and purified by prep-HPLC (column:Phenomenex luna C18 250*50 mm*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 5%-35%, 28 mins) to give the title compound (850 mg, 80%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H),7.33-7.23 (m, 3H), 7.17-7.12 (m, 2H), 6.89-6.84 (m, 2H), 5.44-5.35 (m,1H), 3.87-3.79 (m, 1H), 3.78-3.72 (m, 1H), 3.71-3.69 (m, 3H), 3.68-3.56(m, 4H), 3.53 (s, 2H), 3.34 (s, 3H), 2.93-2.80 (m, 1H), 2.74-2.60 (m,2H), 2.30 (s, 3H), 2.28-2.24 (m, 1H), 2.21-2.18 (m, 1H), 2.18-2.15 (m,1H), 2.05-2.00 (m, 2H), 1.98-1.96 (m, 1H); LC-MS (ESI⁺) m/z 546.3(M+H)⁺.

Step 2—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a mixture of3-[5-[3-[(2S)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (200mg, 367 umol) and (Boc)₂O (96.0 mg, 440 umol) in a mixed solvent of IPA(5 mL) and EA (10 mL) was added Pd(OH)₂/C (0.1 g, 20 wt %) and Pd/C (0.1g, 10 wt %). The reaction mixture was stirred at 25° C. for 12 hoursunder H₂ (50 Psi) atmosphere. On completion, the mixture was filteredand the filtrate was concentrated in vacuo. The residue was purified byreversed phase (0.1% FA) to give the title compound (85.0 mg, 44% yield)as a white solid. LC-MS (ESI⁺) m/z 530.3 (M+H)⁺.

Step3—3-[3-Methyl-5-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate(85.0 mg, 160 umol) in DCM (3 mL) was added TFA (3 mL). The reactionmixture was stirred at 25° C. for 2 hours. On completion, the mixturewas concentrated in vacuo to give the title compound (87.0 mg, 100%yield, TFA) as a yellow solid. LC-MS (ESI⁺) m/z 430.3 (M+H)⁺.

Tert-Butyl N-(4-but-3-ynoxybutyl)-N-methyl-carbamate (Intermediate RS)

To a solution of tert-butyl N-(4-but-3-ynoxybutyl)carbamate (5.00 g,20.7 mmol, Intermediate SY) in THF (100 mL) was added NaH (1.24 g, 31.0mmol, 60% oil dispersion) at 0° C. The mixture was stirred 20° C. for 1hour. Then MeI (4.41 g, 31.0 mmol) was added. The mixture was stirred at20° C. for 15 hrs. On completion, the mixture was quenched by water (10mL) and extracted with EA (2×250 mL). The combined organic layers wereconcentrated in vacuo to give the title compound (5.00 g, 94% yield) asyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.57 (t, J=7.2 Hz, 2H), 3.50 (t,J=6.0 Hz, 2H), 3.24 (s, 2H), 2.85 (s, 3H), 2.48 (dt, J=2.8, 6.8 Hz, 2H),2.03-1.96 (m, 1H), 1.62-1.56 (m, 4H), 1.47 (s, 9H).

3-[3-Methyl-5-[4-[4-(methylamino)butoxy]butyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate RT)

Step 1—Tert-ButylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]but-3-ynoxy]butyl]-N-methyl-carbamate

A mixture of tert-butyl N-(4-but-3-ynoxybutyl)-N-methyl-carbamate (3.06g, 12.0 mmol, Intermediate RS),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.50g, 4.44 mmol, Intermediate HN), Pd(PPh₃)₂Cl₂ (934 mg, 1.33 mmol), CuI(253 mg, 1.33 mmol) and TEA (8.08 g, 79.8 mmol) in DMF (30 mL) wasdegassed and purged with N₂ for 3 times. Then the mixture was stirred at85° C. for 4 hrs under N₂ atmosphere. On completion, the mixture wasdiluted with water (100 mL) and extracted with EA (2×200 mL). Theorganic layer was concentrated in vacuo. The residue was purified byreversed phase (0.1% FA) to give the title compound (1.1 g, 46% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.24 (s,1H), 7.14-7.05 (m, 2H), 5.38 (dd, J=5.2, 12.8 Hz, 1H), 3.56 (t, J=6.8Hz, 2H), 3.46 (t, J=6.0 Hz, 2H), 3.33 (s, 3H), 3.17 (t, J=6.4 Hz, 2H),2.93-2.90 (m, 1H), 2.74 (s, 3H), 2.69-2.63 (m, 2H), 2.53-2.51 (m, 2H),2.08-2.00 (m, 1H), 1.56-1.45 (m, 4H), 1.37 (s, 9H); LC-MS (ESI⁺) m/z535.3 (M+Na)⁺.

Step 2—Tert-ButylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butyl]-N-methyl-carbamate

To a solution of tert-butylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]but-3-ynoxy]butyl]-N-methyl-carbamate (1.10 g, 2.15 mmol) in THF (30 mL)was added Pd/C (0.10 g, 10 wt %) and Pd(OH)₂/C (0.10 g, 10 wt %). Themixture was stirred at 30° C. for 16 hrs under H₂ (15 psi). Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo to give the title compound (1.10 g, 100% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.06-6.94 (m, 2H),6.90-6.83 (m, 1H), 5.34 (dd, J=5.2, 12.8 Hz, 1H), 3.40-3.34 (m, 4H),3.32 (s, 3H), 3.15 (t, J=6.8 Hz, 2H), 2.92-2.88 (m, 1H), 2.74 (s, 3H),2.64-2.58 (m, 4H), 2.07-1.95 (m, 1H), 1.67-1.58 (m, 2H), 1.57-1.43 (m,6H), 1.37 (s, 9H); LC-MS (ESI⁺) m/z 539.2 (M+Na)⁺.

Step3—3-[3-Methyl-5-[4-[4-(methylamino)butoxy]butyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butyl]-N-methyl-carbamate (1.10 g, 2.13 mmol) in DCM (20 mL) wasadded HCl/dioxane (4 M, 5 mL). The mixture was stirred at 25° C. for 3hrs. On completion, the mixture was concentrated in vacuo to give thetitle compound (1.10 g, 100% yield) as yellow solid. LC-MS (ESI⁺) m/z417.2 (M+H)⁺.

4-(4-(2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(difluoromethyl)-1H-pyrazol-1-yl)benzoicAcid (Intermediate RU)

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicacid (44.6 mg, 75.1 umol, Intermediate FX) in DCM (1 mL) was added TFA(770 mg, 6.75 mmol) under N₂ atmosphere. The mixture was stirred at 25°C. for 1 hr. On completion, the reaction mixture was concentrated invacuo to give the title compound (41.0 mg, 100% yield, TFA) as colorlessoil. LC-MS (ESI⁺) m/z 495.2 (M+H)⁺.

(S)-tert-Butyl methyl((4-(prop-2-yn-1-yl)morpholin-2-yl)methyl)carbamate(Intermediate RV)

Step 1—(S)-morpholin-2-ylmethanol

To a solution of tert-butyl(2S)-2-(hydroxymethyl)morpholine-4-carboxylate (25.0 g, 115 mmol, CAS#135065-76-8) in DCM (40 mL) was added HCl/dioxane (4 M, 57.5 mL), thereaction mixture was stirred at 25° C. for 2 hrs. On completed, thereaction mixture was concentrated in vacuo to give the title compound(17.0 g, 96% yield, HCl) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.47(s, 1H), 3.92-3.89 (m, 1H), 3.75-3.72 (m, 2H), 3.40-3.37 (m, 2H), 3.13(t, J=2.4, 2H), 2.92-2.6 (m, 2H).

Step 2—(S)-(4-(prop-2-yn-1-yl)morpholin-2-yl)methanol

To a solution of [(2S)-morpholin-2-yl]methanol (12.0 g, 78.1 mmol, HCl)and 3-bromoprop-1-yne (9.29 g, 78.1 mmol) in DMF (200 mL) was addedK₂CO₃ (32.4 g, 234 mmol). The reaction mixture was stirred at 25° C. for12 hrs. On completion, the reaction mixture was diluted with water (300mL) and extracted with EA (3×80 mL). The combined organic layers wasdried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by silica gel chromatography (petroleumether/ethyl acetate=10/1 to 2/1) to give the title compound (10.5 g, 86%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 3.98-3.91 (m, 1H),3.76-3.63 (m, 3H), 3.62-3.56 (m, 1H), 3.31 (d, J=2.4 Hz, 2H), 2.76-2.66(m, 2H), 2.41 (dt, J=3.6, 11.2 Hz, 1H), 2.28 (t, J=2.4 Hz, 1H), 2.22 (t,J=10.4 Hz, 1H), 1.97-1.66 (m, 1H).

Step 3—(S)-(4-(prop-2-yn-1-yl)morpholin-2-yl)methyl Methanesulfonate

To a solution of [(2S)-4-prop-2-ynylmorpholin-2-yl]methanol (2 g, 12.8mmol) in DCM (30 mL) was added TEA (2.61 g, 25.7 mmol) and MsCl (1.62 g,14.1 mmol). The mixture was stirred at 25° C. for 2 hrs. On completion,the reaction mixture was quenched with water (2 mL), and then extractedwith DCM (3×100 mL). The combined organic layers were washed with brine(2×30 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to give the title compound (3.00 g, 99% yield) asa yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.28-4.20 (m, 2H), 3.99-3.91 (m,1H), 3.91-3.81 (m, 1H), 3.71 (dt, J=2.4, 11.2 Hz, 1H), 3.33 (d, J=2.4Hz, 2H), 3.09 (s, 3H), 2.82-2.75 (m, 1H), 2.69 (dd, J=1.2, 11.2 Hz, 1H),2.51-2.36 (m, 1H), 2.33-2.19 (m, 2H).

Step 4—(S)-tert-butylmethyl((4-(prop-2-yn-1-yl)morpholin-2-yl)methyl)carbamate

To a solution of tert-butyl N-methylcarbamate (1.69 g, 12.8 mmol) andNaI (192 mg, 1.29 mmol) in DMF (30 mL) was added NaH (771 mg, 19.2 mmol,60% oil dispersion). The reaction mixture was stirred at 25° C. for 0.5hr. After, [(2S)-4-prop-2-ynylmorpholin-2-yl]methyl methanesulfonate(3.00 g, 12.8 mmol) was added into the mixture. The resulting reactionmixture was stirred 90° C. for 12 hrs. On completion, the reactionmixture was quenched with water (0.1 mL) and concentrated in vacuo. Theresidue was purified by column chromatography (SiO₂, PE:EA=5:1) to givethe title compound (250 mg, 7% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 3.95-3.86 (m, 1H), 3.77-3.61 (m, 2H), 3.47-3.38 (m, 1H),3.32-3.30 (m, 2H), 3.17 (dd, J=2.4, 10.8 Hz, 1H), 2.93 (s, 3H),2.79-2.65 (m, 2H), 2.39 (dt, J=2.4, 11.2 Hz, 1), 2.28-2.26 (m, 1), 2.11(t, J=10.8 Hz, 1), 1.46 (s, 9H).

3-(3-Methyl-5-(3-((R)-2-((methylamino)methyl)morpholino)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(Intermediate RW)

Step 1—Tert-Butyl(((2S)-4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)morpholin-2-yl)methyl)(methyl)carbamate

To a mixture of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (180mg, 532 umol, Intermediate HN), tert-butylN-methyl-N-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (214 mg,798 umol, Intermediate RV), Pd(PPh₃)₂Cl₂ (37.3 mg, 53.2 umol), CuI (10.1mg, 53.2 umol), 4Å molecular sieves (200 mg) and Cs₂CO₃ (693 mg, 2.13mmol) in DMF (10 mL) was de-gassed with N₂ and then heated to 80° C. for2 hours under N₂. On completion, the reaction mixture was concentratedin vacuo. The residue was purified by reversed-phase HPLC (0.1% FA,condition) to give the title compound (150 mg, 42% yield) as yellow oil.LC-MS (ESI⁺) m/z 526.1 (M+H)⁺.

Step 2—Tert-Butyl(((2S)-4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)propyl)morpholin-2-yl)methyl)(methyl)carbamate

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]methyl]-N-methyl-carbamate(150 mg, 228 umol) in THF (20 mL) was added PtO₂ (13.8 mg, 6.10 umol)under N₂ atmosphere. The suspension was degassed and purged with H₂seven times. The mixture was stirred under H₂ (15 Psi) at 25° C. for 2hrs. On completion, the reaction mixture was filtered and concentratedin vacuo to give the title compound (40.0 mg, 310% yield) as colorlessoil. LC-MS (ESI⁺) m/z 530.3 (M+H)⁺.

Step3—3-(3-Methyl-5-(3-((R)-2-((methylamino)methyl)morpholino)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate (40.0 mg, 75.5 umol) inDCM (3 mL) was added TFA (308 mg, 2.70 mmol) under N₂ atmosphere. Themixture was stirred at 25° C. for 15 minutes. On completion, thereaction mixture was concentrated in vacuo to give the title compound(41.0 mg, 100% yield, TFA) as colorless. LC-MS (ESI⁺) m/z 430.2 (M+H)⁺.

2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]aceticAcid (Intermediate RX)

Step 1—Tert-Butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg, 1.77 mmol, Intermediate HP), tert-butyl2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]acetate (1.07 g, 3.55 mmol,synthesized via Steps 1-2 of Example 441, 1-447) in DMF (10 mL) wasadded CuI (67.6 mg, 355 umol), Cs₂CO₃ (2.89 g, 8.87 mmol) andPd(PPh₃)₂Cl₂ (249.08 mg, 355 umol) under N₂. The reaction mixture wasstirred at 80° C. for 3 hours. On completion, the mixture was pouredinto water (30 mL). The aqueous phase was extracted with ethyl acetate(2×30 mL). The combined organic phase was washed with brine (2×30 mL),dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by reversed-phase (0.1% FAcondition) to give the title compound (598 mg, 60% yield) as brown oil.¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 7.16 (d, J=7.6 Hz, 1H), 6.97 (t,J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 5.23-5.15 (m, 1H), 4.46 (s, 2H),4.01 (s, 2H), 3.76 (s, 3H), 3.76-3.66 (m, 12H), 2.99-2.68 (m, 3H),2.29-2.16 (m, 1H), 1.46 (s, 9H).

Step 2—Tert-Butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of tert-butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]acetate (578 mg, 1.03 mmol) in THF (5mL) was added Pd/C (100 mg, 20 wt %) and Pd(OH)₂/C (100 mg, 20 wt %)under N₂. The suspension was degassed under vacuum and purged with H₂gas three times. The mixture was stirred at 20° C. for 12 hours under H₂(15 psi). On completion, the mixture was filtrated and the filtrate wasconcentrated in vacuo to give a title compound (540 mg, 92% yield) asbrown oil. LC-MS (ESI⁺) m/z 586.3 (M+Na)⁺.

Step3—2-[2-[2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a mixture of tert-butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetate(520 mg, 922 umol) in DCM (2 mL) was added TFA (210 mg, 1.85 mmol). Thereaction mixture was stirred at 20° C. for 1 hour. On completion, themixture was concentrated in vacuo to give a residue. The residue waspurified by column chromatography to give the title compound (436 mg,93% yield) as brown oil. LC-MS (ESI⁺) m/z 508.3 (M+H)⁺.

Step 2—Tert-Butyl 4-(trans-4-aminocyclohexyl)piperazine-1-carboxylate

A mixture of tert-butyl4-[4-(benzyloxycarbonylamino)cyclohexyl]piperazine-1-carboxylate (8.00g, 16.4 mmol) and Pd/C (800 mg, 10 wt %) in MeOH (80 mL) was stirred at25° C. for 2 hours under H₂ (15 Psi). On completion, the mixture wasfiltered, and the cake was washed with MeOH (50 mL). The filtrate andwashings were combined and concentrated in vacuo to give the titlecompound (5.30 g, 100% crude yield) as white solid. ¹H NMR (400 MHz,CDCl₃) δ 3.49-3.21 (m, 4H), 2.64-2.58 (m, 1H), 2.54 (m, 4H), 2.31-2.20(m, 1H), 1.88 (t, J=15.2 Hz, 4H), 1.45 (s, 9H), 1.34-1.22 (m, 2H),1.17-1.05 (m, 2H).

2-[4-[4-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]aceticAcid (Intermediate SB)

Step 1—Tert-butyl2-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]zacetate

A mixture of3-[5-[4-(4-aminobutoxy)butyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(200 mg, 455 umol, HCl, Intermediate OD), tert-butyl 2-bromoacetate(80.0 mg, 410 umol, CAS #5292-43-3) and TEA (100 mg, 988 umol) in DMF (2mL) was stirred at 25° C. for 16 hours. On completion, the mixture waspurified by reverse phase flash chromatography (FA condition) to givethe title compound (100 mg, 31% yield) as light yellow gum. ¹H NMR (400MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.02-6.98 (m, 2H), 6.86 (d, J=8.0 Hz,1H), 5.37-5.28 (m, 1H), 3.62-3.57 (m, 2H), 3.34 (s, 3H), 3.32 (m, 4H),2.91-2.83 (m, 1), 2.65-2.56 (m, 6H), 2.04-1.95 (m, 1H), 1.77-1.73 (m,1H), 1.63-1.47 (m, 8H), 1.41 (s, 9H).

Step 2—2-[4-[4-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]acetic Acid

To a solution of tert-butyl 2-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]acetate (125 mg, 176 umol) in DCM (2 mL) was added TFA(1 mL) at 25° C. The mixture was stirred at 25° C. for 6 hours. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (120 mg, crude, TFA) as yellow gum. LC-MS (ESI⁺) m/z 461.2(M+H)⁺.

Tert-Butyl N-(3-but-3-ynoxypropyl)carbamate (Intermediate SD)

Step 1—3-But-3-ynoxypropanenitrile

To a solution of prop-2-enenitrile (2.00 g, 37.6 mmol) and but-3-yn-1-ol(7.93 g, 113 mmol) in THF (40.0 mL) was added NaOMe (203 mg, 3.77 mmol).The mixture was stirred at 25° C. for 16 hrs. On completion, the mixturewas concentrated in vacuo to give the title compound (4.60 g, 99% yield)as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 3.71 (t, J=6.4 Hz, 2H), 3.63(t, J=6.8 Hz, 2H), 2.62 (t, J=6.4 Hz, 2H), 2.52-2.45 (m, 2H), 2.00 (t,J=2.4 Hz, 1H).

Step 2—3-But-3-ynoxypropan-1-amine

To a mixture of diethylsilane (3.58 g, 40.6 mmol) andtris(perfluorophenyl)borane (83.1 mg, 162 umol) in DCM (30.0 mL) wasadded 3-but-3-ynoxypropanenitrile (2.00 g, 16.2 mmol). The mixture wasstirred at 25° C. for 16 hours. Then HCl/dioxane (4.00 M, 20.0 mL) wasadded, and the mixture was stirred for 1 hour. On completion, themixture was concentrated in vacuo. The residue was dissolved in water(10.0 mL), and then extracted with EA (10.0 mL). The aqueous layer wasconcentrated in vacuo to give the title compound (2.30 g, 86% yield,HCl) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 8.06 (s, 2H), 3.80-3.76(m, 2H), 3.63-3.59 (m, 2H), 3.24 (s, 2H), 2.64-2.57 (m, 2H), 2.21-2.15(m, 1H), 2.08-2.04 (m, 2H).

Step 3—Tert-butyl N-(3-but-3-ynoxypropyl)carbamate

To a solution of 3-but-3-ynoxypropan-1-amine (300 mg, 1.83 mmol, HCl) inMeOH (10.0 mL) was added (Boc)₂O (1.00 g, 4.58 mmol) and TEA (371 mg,3.67 mmol). The mixture was stirred at 25° C. for 16 hours. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by silica gel chromatography (PE:EA=5:1) to give the titlecompound (200 mg, 48% yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆)δ 4.85 (s, 1H), 3.51-3.44 (m, 4H), 3.21-3.10 (m, 2H), 2.43-2.38 (m, 2H),1.95-1.90 (m, 1H), 1.75-1.63 (m, 2H), 1.37 (s, 9H).

3-[(5S)-5-(3-bromophenyl)-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(Intermediate SE)

Step 1—(S)-2-bromo-1-(3-bromophenyl)ethanol

To a stirred solution of(S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1 g,3.61 mmol, CAS #112022-81-8) in THF (50 mL) was added BH₃-DMS (10 M, 2.5mL, 25.3 mmol) at 0° C. The mixture was stirred for 0.5 h at 0° C. Tothe reaction mixture was added a solution of2-bromo-1-(3-bromophenyl)ethanone (10 g, 36.1 mmol) in THF (30 mL)dropwise at 0° C. The mixture was stirred for 12 h at rt. To the mixturewas added MeOH dropwise, where the mixture released bubbles of gas.Addition of MeOH was halted after bubbling stopped. Then the mixture wasconcentrated and purified by column (PE/EA=50/1 to 20/1 to 10/1 to 5/1)to give the title compound (10 g, 100% yield) as a white solid. ¹H NMR(400 MHz, CDCl₃) δ 7.56 (t, J=1.8 Hz, 1H), 7.47-7.45 (m, 1H), 7.32-7.30(m, 1H), 7.26-7.22 (m, 1H), 4.90 (d, J=8.7 Hz, 1H), 3.63 (dd, J=10.5,3.4 Hz, 1H), 3.51 (dd, J=10.5, 8.8 Hz, 1H), 2.68 (d, J=1.6 Hz, 1H).

Step 2—(S)-2-amino-1-(3-bromophenyl)ethanol

To a solution of (S)-2-bromo-1-(3-bromophenyl)ethanol (11 g, 90.3 mmol)in MeOH (80 mL) was added NH₃—H₂O (25%, 200 mL) at 0° C. under N₂. Thereaction mixture was stirred for 12 h under N₂ at room temperature. Themixture was concentrated. The solid was washed with EA to give the titlecompound (6.2 g, 74% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.70 (br s, 2H), 7.60 (t, J=1.9 Hz, 1H), 7.54-7.51 (m, 1H), 7.42-7.34(m, 2H), 6.17 (d, J=3.8 Hz, 1H), 4.81-4.79 (m, 1H), 3.09 (dd, J=12.8,3.2 Hz, 1H), 2.87 (dd, J=12.8, 9.6 Hz, 1H).

Step 3—(S)-5-(3-bromophenyl)oxazolidin-2-one

A mixture of (S)-2-amino-1-(3-bromophenyl)ethanol (1 g, 4.63 mmol), CDI(1.1 g, 6.94 mmol) and THF (30 mL) was heated to 80° C. and stirred forovernight at 80° C. under N₂. To the mixture was added H₂O (20 mL), thenthe mixture was extracted with EA (50 mL). The organic layer wasconcentrated and purified by column chromatography on silica gel(PE/EA=2/1 to 1/1) to give the title compound (300 mg, 27% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.55-7.54 (m, 1H), 7.51 (dt,J=6.9, 2.0 Hz, 1H), 7.32-7.29 (m, 2H), 5.60 (t, J=8.0 Hz, 1H), 5.09 (brs, 1H), 4.00 (dt, J=0.6, 8.7 Hz, 1H), 3.53-3.49 (m, 1H).

Step4—(R)-3-((S)-5-(3-bromophenyl)-2-oxooxazolidin-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of (S)-5-(3-bromophenyl)oxazolidin-2-one (8.1 g, 33.5mmol) in THF (100 mL) was added t-BuOK (5.6 g, 50.3 mmol) at 0° C. underN₂. The mixture was stirred for 1 h at 0° C. Then to the mixture wasadded 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (14 g, 36.8 mmol) at 0° C. under N₂. Themixture was stirred for 2 h at 0° C.˜10° C. To the mixture was added EA(100 mL), then the solution was washed with H₂O (100 mL), brine (50 mL),dried over Na₂SO₄, filtered, concentrated and purified by columnchromatography on silica gel (PE/EA=2/1) to give a mixture of desiredproduct and starting material. Then the mixture was re-purified by flashcolumn chromatography (210 nm, 30% MeCN in H₂O) to give product(R)-3-((S)-5-(3-bromophenyl)-2-oxooxazolidin-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(4.0 g, 25% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.57(m, 2H), 7.39-7.36 (m, 2H), 7.32-7.28 (m, 2H), 6.81-6.77 (m, 2H), 5.48(t, J=8.4 Hz, 1H), 4.87 (s, 2H), 4.69 (dd, J=13.5, 5.2 Hz, 1H), 3.79 (t,J=8.4 Hz, 1H), 3.76 (s, 3H), 3.42 (t, J=8.0 Hz, 1H), 2.95 (ddd, J=17.8,4.5, 2.4 Hz, 1H), 2.77 (ddd, J=17.8, 13.5, 5.5 Hz, 1H), 2.24-2.07 (m,2H).

Step5—(R)-3-((S)-5-(3-bromophenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione

To a solution of(R)-3-((S)-5-(3-bromophenyl)-2-oxooxazolidin-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(4.0 g, 8.47 mmol) in MeCN (90 mL) was added dropwise a solution of CAN(18.6 g, 33.9 mmol) in H₂O (20 mL) at 0° C. The mixture was stirred for3 h at 0° C.˜10° C. To the mixture was added H₂O (50 mL), then thesolution was extracted with EA (100 mL). The organic layer was washedwith brine (30 mL), dried over Na₂SO₄, filtered, concentrated to give ayellow solid. The solid was washed with EA (30 mL) to give the titlecompound (1.2 g, 40% yield) as a white solid. The filtrate wasconcentrated and purified by flash (210 nm, 30% MeCN in H₂O) to giveanother portion of the title compound (0.2 g, 7% yield) as a whitesolid, the total yield is 47%. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s,1H), 7.72 (t, J=1.6 Hz, 1H), 7.63-7.60 (m, 1H), 7.50-7.49 (m, 1H), 7.42(t, J=8 Hz, 1H), 5.63 (dd, J=7.6, 8.8 Hz, 1H), 4.71 (dd, J=5.2, 13.2 Hz,1H), 3.94 (t, J=8.8 Hz, 1H), 3.29-3.25 (m, 1H), 2.92-2.82 (m, 1H),2.59-2.57 (m, 1H), 2.25-2.14 (m, 1H), 2.03-2.01 (m, 1H). LC/MS (ESI,m/z): [M+1]⁺=355.0.

3-[(5S)-5-[3-[4-(3-aminopropoxy)but-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(Intermediate SF)

Step 1—Tert-butylN-[3-[4-[3-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl]but-3-ynoxy]propyl]carbamate

To a solution of tert-butyl N-(3-but-3-ynoxypropyl)carbamate (146 mg,645 umol, Intermediate SD) and3-[(5S)-5-(3-bromophenyl)-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(190 mg, 537 umol, Intermediate SE) in DMF (8.00 mL) was addedPd(PPh₃)₂Cl₂ (37.7 mg, 53.8 umol), CuI (10.2 mg, 53.8 umol), Cs₂CO₃ (701mg, 2.15 mmol) and 4Å molecular sieves (30 mg) under N₂, and the mixturewas stirred at 80° C. for 3 hrs. On completion, the mixture was filteredand the filtrate was concentrated in vacuo. The mixture was purified byprep-HPLC (reverse phase: 0.10% FA) to give the title compound (140 mg,52% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.0 (s, 1H),7.51-7.39 (m, 4H), 6.79 (s, 1H), 5.73-5.58 (m, 1), 4.76-4.63 (m, 1),3.97-3.84 (m, 1), 3.59-3.51 (m, 2H), 3.46-3.43 (m, 2H), 3.30-3.22 (m,1), 3.03-2.95 (m, 2H), 2.92-2.76 (m, 1), 2.70-2.67 (m, 2H), 2.61-2.54(m, 1), 2.28-2.14 (m, 1H), 2.05-1.93 (m, 1H), 1.68-1.57 (m, 2H), 1.38(s, 9H).

Step2—3-[(5S)-5-[3-[4-(3-aminopropoxy)but-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[4-[3-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl]but-3-ynoxy]propyl]carbamate (110 mg, 220 umol) in DCM (4.00 mL) wasadded TFA (6.16 g, 54.0 mmol). The reaction mixture was stirred at 25°C. for 1 hr. On completion, the mixture was concentrated in vacuo togive the title compound (110 mg, 97% yield, TFA) as yellow solid. LC-MS(ESI⁺) m/z 400.2 (M+H)⁺.

But-3-ynyl Methanesulfonate (Intermediate SG)

To a solution of but-3-yn-1-ol (10.0 g, 142 mmol, CAS #927-74-2) and TEA(43.3 g, 428 mmol) in DCM (250 mL) was added MsCl (21.2 g, 185 mmol)dropwise at 0° C. The mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was quenched by water (150 mL) at 0° C.The organic layers were washed with water (150 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (20.0 g,95% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) 4.31 (t, J=6.4Hz, 2H), 3.06 (s, 3H), 2.68-2.64 (M, 2H), 2.07 (t, J=2.8 Hz, 1H).

Tert-Butyl N-[(1-but-3-ynyl-4-piperidyl)methyl]-N-methyl-carbamate(Intermediate

To a solution of tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate(3.00 g, 13.1 mmol, CAS #138200-04-5) in a mixed solvent of CHCl₃ (25mL) and ACN (25 mL) was added K₂CO₃ (3.63 g, 26.2 mmol) and but-3-ynylmethanesulfonate (2.53 g, 17.0 mmol, Intermediate SG). The mixture wasstirred at 70° C. for 16 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give a residue. The residue waspurified by column chromatography (SiO₂, PE/EA=6/1) to give the titlecompound (2.30 g, 62% yield) as light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 3.09 (d, J=6.8 Hz, 2H), 2.97-2.97 (m, 2H), 2.84 (s, 3H), 2.59(t, J=8.0 Hz, 2H), 2.45-2.32 (m, 2H), 2.04-1.93 (m, 3H), 1.65-1.55 (m,3H), 1.45 (s, 9H), 1.30-1.20 (m, 2H).

3-[3-Methyl-5-[4-[4-(methylaminomethyl)-1-piperidyl]but-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate SI)

Step 1—Tert-butylN-[[1-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]but-3-ynyl]-4-piperidyl]methyl]-N-methyl-carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HN) and tert-butylN-[(1-but-3-ynyl-4-piperidyl)methyl]-N-methyl-carbamate (1.04 g, 3.70mmol, Intermediate SH) in DMF (15 mL) was added Cs₂CO₃ (1.93 g, 5.91mmol), CuI (56.3 mg, 295 umol), 4Å molecular sieves (500 mg) andPd(PPh₃)₂Cl₂ (207 mg, 295 umol). The mixture was stirred at 80° C. for 2hours. On completion, the reaction mixture was filtered and concentratedin vacuo; the residue was diluted with water (30 mL), and then extractedwith EA (3×40 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (FA condition) to give the title compound (80.0mg, 10% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1H),7.14 (dd, J=1.6, 8.4 Hz, 1H), 7.07 (s, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.19(dd, J=5.6, 12.8 Hz, 1H), 3.42 (s, 3H), 3.12 (d, J=6.8 Hz, 2H),3.07-2.92 (m, 3H), 2.89-2.81 (m, 4H), 2.80-2.58 (m, 5H), 2.29-2.21 (m,1H), 2.19-2.00 (m, 2H), 1.46 (s, 9H), 1.39-1.24 (m, 2H); LC-MS (ESI⁺)m/z 538.3 (M+H)⁺.

Step2—3-[3-Methyl-5-[4-[4-(methylaminomethyl)-1-piperidyl]but-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[1-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]but-3-ynyl]-4-piperidyl]methyl]-N-methyl-carbamate(60.0 mg, 111 umol) in DCM (3 mL) was added TFA (924 mg, 8.10 mmol). Themixture was stirred at 30° C. for 1 hour. On completion, the reactionmixture was concentrated in vacuo to give the title compound (60.0 mg,97% yield, TFA) as light yellow oil. LC-MS (ESI⁺) m/z 438.3 (M+H)⁺.

Tert-Butyl N-[3-(2-piperazin-1-ylethoxy)cyclobutyl]carbamate(Intermediate SJ)

Step 1—Ethyl 2-[3-(tert-butoxycarbonylamino)cyclobutoxy]acetate

To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (8.00 g,43.0 mmol, CAS #389890-42-0) in DCM (80 mL) was added diacetoxy rhodium(0.38 g, 0.85 mmol), the mixture was stirred at 25° C. for 0.5 hour.Then a solution of ethyl 2-diazoacetate (5.90 g, 51.0 mmol, CAS#623-73-4) in DCM (20 mL) was added to the reaction mixture and stirredat 25° C. for 12 hours. On completion, the reaction mixture was dilutedwith saturated sodium bicarbonate solution (100 mL) and extracted withDCM (2×150 mL). The combined organic layers were washed with brine(2×200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by column chromatography togive the title compound (9.00 g, 77% yield) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ 4.23-4.19 (m, 4H), 3.97 (s, 2H), 2.45-2.41 (m, 2H),2.17-2.14 (m, 2H), 1.43 (m, 9H), 1.30-1.28 (m, 3H).

Step 2—Tert-Butyl N-[3-(2-hydroxyethoxy)cyclobutyl]carbamate

To a solution of ethyl2-[3-(tert-butoxycarbonylamino)cyclobutoxy]acetate (9.00 g, 33.0 mmol)in THF (100 mL) was added LiBH₄ (1.20 g, 53.0 mmol) at 0° C. Thereaction mixture was stirred at 25° C. for 2 hours. On completion, thereaction mixture was quenched by H₂O (60 mL) at 25° C., and thenextracted with ethyl acetate (2×100 mL). The combined organic layerswere washed with (2×200 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (7.0 g, 92% yield) ascolorless oil.

Step 3—2-[3-(Tert-butoxycarbonylamino)cyclobutoxy]ethyl methanesulfonate

To a solution of tert-butyl N-[3-(2-hydroxyethoxy)cyclobutyl]carbamate(2.00 g, 8.70 mmol) in DCM (20 mL) was added Et₃N (1.80 g, 17.0 mmol)and MsCl (1.50 g, 13.0 mmol) at 0° C. Then the reaction mixture wasstirred at 25° C. for 1 hour. On completion, the reaction mixture wasdiluted with H₂O (50 mL) and extracted with DCM (2×50 mL). The combinedorganic layers were washed with brine (2×100 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (2.00 g,75% yield) as colorless oil.

Step 4—Benzyl4-[2-[3-(tert-butoxycarbonylamino)cyclobutoxy]ethyl]piperazine-1-carboxylate

To a solution of 2-[3-(tert-butoxycarbonylamino)cyclobutoxy]ethylmethanesulfonate (2.00 g, 6.50 mmol) and benzylpiperazine-1-carboxylate(2.90 g, 13.0 mmol, CAS #31166-44-6) in ACN (40 mL) was added Et₃N (2.00g, 19.0 mmol) and KI (1.30 g, 7.80 mmol). Then the reaction mixture wasstirred at 70° C. for 12 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give a residue. The crude productwas purified by reverse phase HPLC (0.1% FA condition) to give the titlecompound (2.00 g, 77% yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆)δ 7.39-7.33 (m, 5H), 7.18 (d, J=6.0 Hz, 1H), 5.11 (s, 2H), 4.06-4.00 (m,3H), 3.57 (d, J=4.0 Hz, 2H), 3.31 (s, 3H), 3.11 (d, J=9.2 Hz, 2H), 2.52(s, 4H), 2.22-2.18 (m, 2H), 2.12-2.08 (m, 2H), 1.37 (s, 9H); LC-MS(ESI⁺) m/z 434.3 (M+H).

Step 5—Tert-Butyl N-[3-(2-piperazin-1-ylethoxy)cyclobutyl]carbamate

To a solution of benzyl4-[2-[3-(tert-butoxycarbonylamino)cyclobutoxy]ethyl]piperazine-1-carboxylate(1.50 g, 3.50 mmol) in MeOH (20 mL) was added Pd/C (0.200 g, 3.50 mmol,10 wt %). Then the reaction mixture was degassed and purged with H₂ gas3 times and stirred at 25° C. for 12 hours under H₂ (15 psi) atmosphere.On completion, the reaction mixture was filtered and concentrated invacuo to give the title compound (1.0 g, 97% yield) as colorless oil.

1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde(Intermediate SK)

Step 1—3-(3-Methyl-2-oxo-5-vinyl-benzimidazol-1-yl)piperidine-2,6-dione

A mixture of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (3.00g, 8.87 mmol, Intermediate HN), potassium hydride, trifluoro(vinyl)boron (3.57 g, 26.6 mmol), Cs₂CO₃ (2 M solution, 8.87 mL),Pd(dppf)Cl₂·CH₂Cl₂ (724 mg, 887 umol) and in dioxane (30 mL) wasdegassed and purged with N₂ for 3 times, and then the mixture wasstirred at 80° C. for 3 hours under N₂ atmosphere. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (TFA condition) to give the titlecompound (1.60 g, 58% yield) as a yellow solid. LC-MS (ESI⁺) m/z 286.0(M+H)⁺.

Step2—1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde

To a solution of3-(3-methyl-2-oxo-5-vinyl-benzimidazol-1-yl)piperidine-2,6-dione (0.30g, 1.05 mmol) in a mixed solvent of dioxane (20 mL) and H₂O (2 mL) wasadded NaIO₄ (449 mg, 2.10 mmol), OsO₄ (267 mg, 1.00 mmol) and NMO (61.0mg, 525 umol). The mixture was stirred at 25° C. for 0.5 hr. Oncompletion, the residue was diluted with water (10 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was purified by prep-HPLC (TFAcondition) to give the title compound (0.1 g, 32% yield) as a graysolid. LC-MS (ESI⁺) m/z 288.0 (M+H)⁺.

3-[5-[[4-[2-(3-Aminocyclobutoxy)ethyl]piperazin-1-yl]methyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate SL)

Step1—Tert-butylN-[3-[2-[4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]piperazin-1-yl]ethoxy]cyclobutyl]carbamate

To a solution of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde(0.20 g, 696 umol, Intermediate SK) andtert-butyl-N-[3-(2-piperazin-1-ylethoxy)cyclobutyl]carbamate (0.420 g,1.40 mmol, Intermediate SJ) in THF (4 mL) was added HOAc (84.0 mg, 1.40mmol) and stirred at 40° C. for 1 hour. Then NaBH(OAc)₃ (0.440 g, 2.10mmol) was added to the reaction mixture and stirred at 40° C. for 12hrs. On completion, the reaction mixture was concentrated in vacuo togive a residue. The residue was purified by prep-HPLC (column: Luna C18150*25 5u; mobile phase: [water (0.075% TFA)-ACN]; B %: 15%-45%, 9 min)to give the title compound (0.21 g, 46% yield) as a colorless oil. LC-MS(ESI⁺) m/z 571.2 (M+H)⁺.

Step2—3-[5-[[4-[2-(3-Aminocyclobutoxy)ethyl]piperazin-1-yl]methyl]-3-methyl-2-oxo-Benzimidazol-1-yl]piperidine-2,6-dione

To a solution oftert-butylN-[3-[2-[4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]piperazin-1-yl]ethoxy]cyclobutyl]carbamate (0.35 g, 0.61 mmol) inDCM (6 mL) was added HCl/dioxane (4 M, 3.1 mL). Then the reactionmixture was stirred at 25° C. for 0.5 hour. On completion, the reactionmixture was concentrated in vacuo to give the title compound (0.1 g, 34%yield, HCl) as colorless oil. LC-MS (ESI⁺) m/z 471.2 (M+H)⁺.

3-[(5S)-5-[3-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]prop-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(Intermediate SM)

Step 1—Tert-butylN-[[(2S)-4-[3-[3-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate

To a mixture of tert-butylN-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (540 mg, 2.12mmol, synthesized via Step 1 of Intermediate RK) and3-[(5S)-5-(3-bromophenyl)-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(300 mg, 849 umol, Intermediate SE) in DMF (5 mL) was added Pd(PPh₃)₂Cl₂(59.6 mg, 84.9 umol), CuI (16.1 mg, 84.9 umol) and Cs₂CO₃ (1.38 g, 4.25mmol). The reaction mixture was stirred at 80° C. for 2 hours under N₂atmosphere. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was diluted with water (30 mL) andextracted with EA (3×30 mL). The combined organic layers was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (450 mg, 95% yield) as light yellow solid. LC-MS (ESI⁺)m/z 527.3 (M+H)⁺.

Step2—3-[(5S)-5-[3-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]prop-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[[(2S)-4-[3-[3-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate (180 mg, 341 umol) inDCM (3 mL) was added TFA (4.62 g, 40.5 mmol, 3 mL). The reaction mixturewas stirred at 25° C. for 0.5 hour. On completion, the reaction mixturewas concentrated in vacuo to give the title compound (184 mg, 99% yield,TFA) as red oil. LC-MS (ESI⁺) m/z 427.1 (M+H)⁺.

3-[(5S)-5-(4-bromophenyl)-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(Intermediate SN)

Step 1—(S)-2-bromo-1-(4-bromophenyl)ethanol

To a stirred solution of(S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.5g, 1.81 mmol) in THF (25 mL) was added BH₃-DMS (10 M, 1.3 mL, 12.7 mmol)at 0° C. The mixture was stirred for 0.5 h at 0° C. To the reactionmixture was then added a solution of 2-bromo-1-(4-bromophenyl)ethanone(5 g, 18.1 mmol) in THF (15 mL) dropwise at 0° C. The mixture wasstirred for 12 h at rt. To the mixture was then added MeOH dropwisewhere gas evolved. MeOH was added until no more bubbling occurred. Themixture was concentrated and purified by column chromatography on silicagel (PE/EA=50/1 to 20/1 to 10/1 to 5/1) to give the title compound (5 g,100% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.55-7.52 (m,2H), 7.38-7.34 (m, 2H), 5.89 (d, J=4.9 Hz, 1H), 4.82-4.78 (m, 1H), 3.66(dd, J=10.2, 4.6 Hz, 1H), 3.57 (dd, J=10.2, 6.8 Hz, 1H).

Step 2—(S)-2-amino-1-(4-bromophenyl)ethanol

To a solution of (S)-2-bromo-1-(4-bromophenyl)ethanol (15 g, 123 mmol)in MeOH (100 mL) was added NH₃—H₂O (25%, 250 mL) at 0° C. under N₂. Thereaction mixture was stirred at rt for 12 h under N₂. Then the mixturewas concentrated. The solid was washed with EA to give the titlecompound (8.4 g, 74% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 7.54 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H), 5.51 (br s, 3H), 4.64(dd, J=8.4, 3.6 Hz, 1H), 2.83 (dd, J=12.8, 3.4 Hz, 1H), 2.69 (dd,J=12.6, 6.8 Hz, 1H).

Step 3—(S)-5-(4-bromophenyl)oxazolidin-2-one

A mixture of (S)-2-amino-1-(4-bromophenyl)ethanol (22 g, 102 mmol), CDI(24.2 g, 153 mmol) and THF (500 mL) was heated to 80° C. and stirred forovernight at 80° C. under N₂. To the mixture was then added H₂O (200mL), and the mixture was extracted with EA (300 mL). The organic layerwas concentrated and purified by column (PE/EA=2/1 to 1/1) to give thetitle compound (8.0 g, 33% yield) as a yellow solid.

Step4—(R)-3-((S)-5-(4-bromophenyl)-2-oxooxazolidin-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of (S)-5-(3-bromophenyl)oxazolidin-2-one (8.0 g, 30.2mmol) in THF (100 mL) was added t-BuOK (5.5 g, 49.8 mmol) at 0° C. underN₂. The mixture was stirred for 1 h at 0° C. Then to the mixture wasadded 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (13.9 g, 36.8 mmol) at 0° C. under N₂. Themixture was stirred at 0° C.˜10° C. for 2 h. To the mixture was thenadded EA (100 mL), the solution was then washed with H₂O (100 mL), brine(50 mL), dried over Na₂SO₄, filtered, concentrated and purified bycolumn chromatography on silica gel (PE/EA=2/1) to give a mixture ofdesired product(R)-3-((S)-5-(4-bromophenyl)-2-oxooxazolidin-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dioneand starting material. Then the mixture was re-purified by flash columnchromatography (210 nm, 30% MeCN in H₂O) to give the title compound (4.5g, 28% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.57-7.52 (m,2H), 7.34-7.29 (m, 2H), 7.26-7.24 (m, 2H), 6.86-6.80 (m, 2H), 5.89 (dd,J=8.7, 7.1 Hz, 1H), 4.89 (s, 2H), 4.58 (dd, J=12.8, 6.0 Hz, 1H), 3.94(t, J=8.4 Hz, 1H), 3.78 (s, 3H), 3.80 (dd, J=17.9, 7.1 Hz, 1H),2.97-2.90 (m, 1H), 2.79-2.70 (m, 1H), 2.20-2.04 (m, 2H).

Step5—(R)-3-((S)-5-(4-bromophenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione

To a solution of(R)-3-((S)-5-(4-bromophenyl)-2-oxooxazolidin-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(50 mg, 0.106 mmol) in MeCN (5 mL) was added dropwise a solution of CAN(232 mg, 0.424 mmol) in H₂O (1 mL) at 0° C. The mixture was stirred for3 h at 0° C.˜10° C. To the mixture was then added H₂O (100 mL), and thesolution was extracted with EA (200 mL). The organic layer was washedwith brine (50 mL), dried over Na₂SO₄, filtered, concentrated andpurified by column (PE/EA=1/1) to give the title compound (5 mg, 14%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.56(d, J=8.0 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 5.49 (t, J=8.2 Hz, 1H), 4.74(dd, J=13.0, 5.2 Hz, 1H), 3.84 (t, J=8.4 Hz, 1H), 3.48 (t, J=7.8 Hz,1H), 2.91-2.87 (m, 1H), 2.82-2.73 (m, 1H), 2.22-2.11 (m, 2H). LC/MS(ESI, m/z): [M+1]⁺=355.0.

Step6—(S)-3-((S)-5-(4-bromophenyl)-2-oxooxazolidin-3-yl)piperidine-2,6-dione

To a solution of(S)-3-((S)-5-(4-bromophenyl)-2-oxooxazolidin-3-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(80 mg, 0.169 mmol) in MeCN (10 mL) was added dropwise a solution of CAN(372 mg, 0.678 mmol) in H₂O (2 mL) at 0° C. The mixture was stirred for3 h at 0° C.˜10° C. To the mixture was added H₂O (100 mL), then themixture was extracted with EA (200 mL). The organic layer was washedwith brine (50 mL), dried over Na₂SO₄, filtered, concentrated andpurified by column (PE/EA=1/1) to give the title compound (1.5 mg, 3%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.86 (s, 1H), 7.56(d, J=8.2 Hz, 2H), 7.26-7.22 (m, 2H), 5.60 (t, J=7.8 Hz, 1H), 4.64 (dd,J=12.0, 5.2 Hz, 1H), 4.00 (t, J=8.2 Hz, 1H), 3.41 (t, J=7.4 Hz, 1H),2.91-2.86 (m, 1H), 2.78-2.73 (m, 1H), 2.24-2.20 (m, 2H). LC/MS (ESI,m/z): [M+1]⁺=355.0.

3-[(5S)-5-[4-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]prop-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(Intermediate SO)

Step 1—Tert-ButylN-[[(2S)-4-[3-[4-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (648 mg, 2.55mmol, synthesized via Step 1 of Intermediate RK) and3-[(5S)-5-(4-bromophenyl)-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(300 mg, 849 umol, Intermediate SN) in DMF (15 mL) was addedPd(PPh₃)₂Cl₂ (119 mg, 169 umol), CuI (32.3 mg, 169 umol) and Cs₂CO₃(1.38 g, 4.25 mmol). The reaction mixture was stirred at 80° C. for 2hours under N₂. On completion, the mixture was filtered and the filtratewas concentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (440 mg,80% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.00 (d, J=6.0Hz, 1H), 7.53-7.40 (m, 4H), 6.88-6.84 (m, 1H), 5.73-5.61 (m, 1H),4.75-4.63 (m, 1H), 3.94 (t, J=8.8 Hz, 1H), 3.89 (t, J=8.8 Hz, 1H), 3.80(t, J=7.2 Hz, 2H), 3.50-3.40 (m, 4H), 3.30-3.21 (m, 2H), 2.60-2.52 (m,2H), 2.37-2.15 (m, 3H), 2.02-1.92 (m, 2H), 1.36 (s, 9H); LC-MS (ESI⁺)m/z 527.3 (M+H)⁺.

Step2—3-[(5S)-5-[4-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]prop-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[3-[4-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl] prop-2-ynyl]morpholin-2-yl]methyl]carbamate (150 mg, 284 umol)in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol, 1 mL). The reactionmixture was stirred at 25° C. for 2 hours. On completion, the residueconcentrated in vacuo to give the title compound (150 mg, 97% yield) asyellow oil. LC-MS (ESI⁺) m/z 427.2 (M+H)⁺.

3-[3-Methyl-4-[3-[2-[2-(methylamino)ethoxy]ethoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate SP)

Step 1—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethyl]-N-methyl-carbamate

To a mixture of tert-butylN-methyl-N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (1.37 g, 5.32 mmol,Intermediate FY),3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg, 1.77 mmol, Intermediate HP) in DMF (30 mL) was added Cs₂CO₃ (2.89 g,8.87 mmol), Pd(PPh₃)₂Cl₂ (249 mg, 354 umol) and CuI (67.5 mg, 354 umol)under N₂. The reaction mixture was stirred at 80° C. for 2 hours. Oncompletion, the mixture was filtered, the filtrate was poured into water(100 mL), and the aqueous phase was extracted with ethyl acetate (2×40mL). The combined organic phase was washed with brine (2×40 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated in vacuo to getresidue. The residue was purified by reverse phase (0.1% FA condition)to get title compound (480 mg, 52% yield) as a brown solid. ¹H NMR (400MHz, CDCl₃) δ 8.29 (s, 1H), 7.22-7.16 (m, 1H), 7.03-7.00 (m, 1H), 6.78(d, J=8.0 Hz, 1H), 5.28-5.17 (m, 1H), 4.49 (s, 2H), 4.20-4.08 (m, 1H),3.81-3.78 (m, 3H), 3.71-3.67 (m, 2H), 3.62 (s, 3H), 3.61-3.55 (m, 4H),2.93 (s, 3H), 2.92 (s, 2H), 2.30-2.20 (m, 1H), 2.03 (s, 1H), 1.47 (s,9H).

Step 2—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]-N-methyl-carbamate

To a mixture of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethyl]-N-methyl-carbamate(480 mg, 933 umol) in THF (20 mL) was added Pd/C (100 mg, 1.87 mmol, 10wt %) and Pd(OH)₂/C (100 mg, 1.87 mmol, 10 wt %) under N₂. Thesuspension was degassed in vacuo and purged with H₂ gas three times. Themixture was stirred at 20° C. for 12 hours under H₂ (15 psi). Oncompletion, the mixture was filtered and concentrated in vacuo to givethe title compound (360 mg, 74% yield) as brown oil. LC-MS (ESI⁺) m/z541.2 (M+Na)⁺.

Step3—3-[3-Methyl-4-[3-[2-[2-(methylamino)ethoxy]ethoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]-N-methyl-carbamate (350 mg, 675 umol) in DCM (2mL) was added TFA (154 mg, 1.35 mmol). The reaction mixture was stirredat 25° C. for 0.1 hour. On completion, the mixture was concentrated invacuo to get title compound (365 mg, 100% yield) as brown oil. LC-MS(ESI⁺) m/z 419.1 (M+H)⁺.

3-[4-[3-[(2R)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate SO)

Step 1—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (940 mg, 3.70mmol, synthesized via Step 1 of Intermediate RJ) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP) in DMF (15 mL) was added Cs₂CO₃ (2.41 g,7.39 mmol), CuI (28.1 mg, 147 umol) and Pd(PPh₃)₂Cl₂ (103 mg, 147 umol).The reaction mixture was stirred at 80° C. for 2 hr under N₂. Oncompletion, the mixture was filtered, and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (500 mg, 66% yield) as ayellow solid. LC-MS (ESI⁺) m/z 512.3 (M+H)⁺.

Step 2—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate(500 mg, 977 umol) in THF (20 mL) was added Pd/C (100 mg, 10 wt %) andPd(OH)₂/C (100 mg, 10 wt %). The reaction mixture was stirred at 25° C.under H₂ (15 psi) for 12 hrs. On completion, the residue was filteredand the filtrate was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (370 mg, 73% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 7.04-6.91(m, 2H), 6.91-6.79 (m, 2H), 5.36 (dd,J=5.2, 12.4 Hz, 1H), 3.76 (d, J=10.4 Hz, 1H), 3.56 (s, 3H), 3.46 (t,J=10.8 Hz, 1H), 3.40-3.35 (m, 1H), 3.02-2.79 (m, 6H), 2.75-2.61 (m, 3H),2.45-2.31 (m, 2H), 2.06-1.94 (m, 2H), 1.82-1.63 (m, 3H), 1.37 (s, 9H);LC-MS (ESI⁺) m/z 516.3 (M+H)⁺.

Step3—3-[4-[3-[(2R)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]carbamate (370 mg, 717 umol) in DCM (3 mL)was added HCl/dioxane (4 M, 3.08 mL). The reaction mixture was stirredat 25° C. for 2 hrs. On completion, the mixture was concentrated invacuo to give the title compound (320 mg, 98% yield, HCl) as a whitesolid. LC-MS (ESI⁺) m/z 416.3 (M+H)⁺.

3-[4-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate SR)

Step 1—Tert-ButylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP) and tert-butylN-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (564 mg, 2.22mmol, synthesized via Step 1 of Intermediate RK) in DMF (20 mL) wasadded Cs₂CO₃ (1.93g, 5.91 mmol), CuI (56.3 mg, 295 umol), 4Å molecularsieves (20 mg) and Pd(PPh₃)₂Cl₂ (207 mg, 295 umol), and the mixture washeated at 80° C. for 2 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo. The residue was diluted with water(40 mL), and then extracted with EA (50 mL×3). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo togive a residue. The residue was purified by prep-HPLC (FA condition) togive the title compound (430 mg, 56% yield) as light yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.35 (s, 1H), 7.18 (dd, J=0.8, 8.0 Hz, 1H), 7.98(t, J=8.0 Hz, 1), 6.77 (dd, J=0.8, 8.0 Hz, 1H), 5.22 (dd, J=5.2, 12.8Hz, 1H), 4.90 (s, 1H), 3.94 (dd, J=0.8, 11.6 Hz, 1), 3.77 (s, 3H),3.74-3.70 (m, 1), 3.68-3.62 (m, 1), 3.58 (d, J=2.0 Hz, 2H), 3.40-3.31(m, 1), 3.18-3.08 (m, 1), 3.01-2.91 (m, 1), 2.90-2.73 (m, 4H), 2.50-2.44(m, 1), 2.31-2.17 (m, 2H), 1.44 (s, 9H). LC-MS (ESI⁺) m/z 512.3 (M+H)⁺.

Step 2—Tert-ButylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate(360 mg, 703 umol) in THF (5 mL) was added Pd(OH)₂/C (40.0 mg, 10 wt %)and Pd/C (40.0 mg, 10 wt %) under N₂. The suspension was degassed undervacuum and purged with H₂ three times. The mixture was stirred under H₂(15 psi) at 25° C. for 4 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (FA condition) to give the title compound (280 mg,77% yield) as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s,1H), 7.89 (t, J=8.4 Hz, 1H), 7.18 (d, J=0.8, 8.0 Hz, 1H), 6.67 (d, J=7.6Hz, 1), 5.22 (dd, J=5.2, 12.4 Hz, 1H), 4.90 (s, 1), 3.87 (d, J=10.8 Hz,1), 3.72-3.52 (m, 5H), 3.40-3.25 (m, 1H), 3.17-3.03 (m, 1H), 3.01-2.91(m, 3H), 2.87-2.66 (m, 4H), 2.41 (t, J=6.8 Hz, 2H), 2.26-2.08 (m, 2H),1.94-1.83 (m, 3H), 1.45 (s, 9H); LC-MS (ESI⁺) m/z 516.2 (M+H)⁺.

Step3—3-[4-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]carbamate (200 mg, 387 umol) in DCM (3 mL)was added TFA (924 mg, 8.10 mmol). The mixture was stirred at 25° C. for1 hour. On completion, the reaction mixture was concentrated in vacuo togive the title compound (200 mg, 98% yield, TFA) as light yellow oil.LC-MS (ESI⁺) m/z 416.3 (M+H)⁺.

3-[7-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate SS)

Step 1—Tert-butyl(((2S)-4-(3-(3-(2,6-dioxopiperidin-3-yl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)prop-2-yn-1-yl)morpholin-2-yl)methyl)carbamate

To a solution of3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione 2 (600 mg,1.85 mmol, Intermediate JF) and tert-butylN-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (704 mg, 2.77mmol, synthesized via Step 1 of Intermediate RK) in DMF (15 mL) wasadded Cs₂CO₃ (2.41 g, 7.38 mmol), CuI (70.3 mg, 369 umol), 4Å molecularsieves (30.0 mg) and Pd(PPh₃)₂Cl₂ (259 mg, 369 umol) at 25° C. under N₂.Then the mixture was heated at 80° C. for 2 hours. On completion, theresidue was filtered and the filtrate was concentrated in vacuo to givea residue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=1:2 to 1:3) to give the title compound(684 mg, 74% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.18(s, 1H), 7.43 (s, 1H), 7.23-7.20 (m, 1H), 7.14-7.10 (t, J=8.0 Hz, 1H),6.80-6.77 (m, 1H), 5.07-5.02 (m, 1H), 4.91-4.90 (m, 1H), 3.96-3.92 (m,1H), 3.74-3.60 (m, 4H), 3.16-3.09 (m, 1), 3.02-2.97 (m, 1), 2.89-2.68(m, 4H), 2.54-2.47 (m, 1), 2.37-2.21 (m, 2H), 1.44 (s, 9H); LC-MS (ESI⁺)m/z 499.1 (M+H)⁺.

Step2—Tert-butylN-[[(2S)-4-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propyl]morpholin2-yl]methyl]carbamate

To a mixture of tert-butylN-[[(2S)-4-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate(250 mg, 501 umol) in THF (5 mL) was added Pd/C (75.0 mg, 10 wt %) andPd(OH)₂ (75.0 mg, 10 wt %) under N₂. The suspension was degassed invacuo and purged with H₂ three times. The mixture was stirred under H₂(15 psi) at 25° C. for 16 hours. On completion, the reaction mixture wasfiltered to remove Pd/C and Pd(OH)₂/C, and concentrated in vacuo to givea residue. The residue was purified by reverse phase (0.1% FA) to givethe title compound (120 mg, 55% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.38 (s, 1H), 7.10 (t, J=8.0 Hz, 1H), 7.00 (d, J=7.8 Hz,1H), 6.70 (d, J=7.8 Hz, 1H), 5.08-5.04 (m, 1H), 4.89 (s, 1H), 3.92-3.76(m, 3H), 3.34-3.29 (m, 1H), 3.18-3.09 (m, 1H), 3.01-2.69 (m, 8H), 2.57(d, J=5.4 Hz, 2H), 2.36-2.30 (m, 2H), 2.04-1.99 (m, 2H), 1.45 (s, 9H);LC-MS (ESI⁺) m/z 503.1 (M+H)⁺.

Step3—3-[7-[3-[(2S)-2-(aminomethyl)morpholin-4-yl]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[[(2S)-4-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propyl]orpholin-2-yl]methyl]carbamate (140 mg, 278 umol) in DCM (2 mL) wasadded TFA (317 mg, 2.79 mmol) in one portion at 25° C. The mixture wasstirred at 25° C. for 0.5 hour. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (139 mg, 96% yield,TFA) as light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.22 (s, 1H),8.06 (s, 2H), 7.23-7.12 (m, 2H), 7.10-7.00 (m, 1H), 5.40-5.35 (m, 1H),5.41-5.34 (m, 1H), 4.11 (d, J=10.4 Hz, 1H), 4.01-3.89 (m, 1H), 3.74 (t,J=12.0 Hz, 1H), 3.64-3.43 (m, 2H), 3.32-3.11 (m, 2H), 3.11-2.98 (m, 2H),2.97-2.59 (m, 7H), 2.18-2.11 (m, 1H), 2.09-2.00 (m, 2H); LC-MS (ESI⁺)m/z 403.2 (M+H)⁺.

3-[7-[3-[(2R)-2-(aminomethyl)morpholin-4-yl]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate ST)

Step 1—Tert-ButylN-[[(2R)-4-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (488 mg, 1.92mmol, synthesized via Step 1 of Intermediate RJ) and3-(7-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (250 mg, 768umol, Intermediate JF) in DMF (15 mL) was added Pd(PPh₃)₂Cl₂ (53.9 mg,76.9 umol), CuI (14.6 mg, 76.9 umol) and Cs₂CO₃ (1.25 g, 3.84 mmol). Thereaction mixture was stirred at 80° C. for 2 hrs under N₂. Oncompletion, the mixture was filtered, and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (350 mg, 91% yield) as ayellow solid. LC-MS (ESI⁺) m/z 499.2 (M+H)⁺.

Step 2—Tert-ButylN-[[(2R)-4-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2R)-4-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]prop-2-ynyl]morpholin-2-yl]methyl]carbamate (350 mg, 702 umol) in THF(20 mL) was added Pd/C (100 mg, 10 wt %) and Pd(OH)₂/C (100 mg, 10 wt%). The reaction mixture was stirred at 25° C. under H₂ (15 psi) for 12hrs. On completion, the residue was filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (290 mg,82% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H),7.17-7.07 (m, 2H), 7.02 (d, J=6.8 Hz, 1H), 6.82 (t, J=5.6 Hz, 1H),5.38-5.32 (m, 1H), 3.77 (d, J=10.2 Hz, 1H), 3.47 (d, J=11.2 Hz, 1H),3.43-3.39 (m, 1H), 2.99-2.87 (m, 3H), 2.79-2.65 (m, 6H), 2.44-2.31 (m,2H), 2.21-2.07 (m, 2H), 1.87-1.69 (m, 3H), 1.36 (s, 9H); LC-MS (ESI⁺)m/z 503.3 (M+H)⁺.

Step3—3-[7-[3-[(2R)-2-(aminomethyl)morpholin-4-yl]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2R)-4-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-7-yl]propyl]morpholin-2-yl]methyl]carbamate (290 mg, 577 umol) in DCM (3 mL) wasadded HCl/dioxane (4 M, 2.48 mL). The reaction mixture was stirred at25° C. for 2 hrs. On completion, the mixture was concentrated in vacuoto give the title compound (250 mg, 98% yield, HCl) as a white solid.LC-MS (ESI⁺) m/z 403.2 (M+H)⁺.

3-(6-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(Intermediate SU)

Step 1—Tert-Butyl (2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate

To a solution of tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (2 g, 8.03 mmol,synthesized via Step 1 on Intermediate AC) in DCM (20 mL) was addedDess-Martin periodinane (5.1 g, 12.04 mmol) and AcOH (1 mL) portionwise. After addition, the mixture was stirred at rt overnight. Themixture was then concentrated in vacuo. The residue was purified byflash chromatography to give the title compound (300 mg, 15%) as an oil.LC/MS (ESI, m/z): [M+1]⁺=248.2.

Step 2—Tert-Butyl(2-(2-(2-((9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)amino)ethoxy)ethoxy)ethyl)carbamate

To a mixture of3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (200 mg, 0.68mmol, Intermediate UG), tert-butyl(2-(2-(2-oxoethoxy)ethoxy)ethyl)carbamate (176.3 mg, 0.714 mmol) in THF(5 mL) was added AcOH (5 drops). The mixture was stirred at rt for 2 h.Then sodium cyanoborohydride (85.4 mg, 1.36 mmol) was added, and themixture was heated to 40° C. and stirred overnight. Then the mixture waspoured into water, and extracted with EtOAc (3×30 mL). The combinedorganic layers were washed with brine (50 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byprep HPLC to give the title compound (70 mg, 20% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (br. s., 1H), 8.52-8.26 (m,2H), 7.36-7.32 (m, 2H), 7.15 (dd, J=7.63, 4.88 Hz, 1H), 6.93-6.90 (m,1H), 6.78-6.76 (m, 1H), 5.91 (br. s., 1H), 5.30 (br. s., 1H), 3.64(t,J=5.82 Hz, 2H), 3.51-3.59 (m, 4H), 3.40 (t, J=6.13 Hz, 2H), 3.30-3.28(m, 2H), 3.09-2.98 (m, 4H), 2.69-2.66 (m, 1H), 2.00-2.12 (m, 1H), 1.37(s, 9H); LC/MS (ESI, m/z): [M+1]⁺=526.55.

Step3—3-(6-((2-(2-(2-Aminoethoxy)ethoxy)ethyl)amino)-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[2-[[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]amino]ethoxy]ethoxy]ethyl]carbamate (20.0 mg, 38.0 umol) in DCM (3 mL) wasadded HCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 25°C. for 0.5 hr. On completion, the reaction mixture was concentrated invacuo to give the title compound (17.5 mg, 100% yield, HCl) as a whitesolid. LC-MS (ESI⁺) m/z 426.2 (M+H)⁺.

3-[4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]-1-methyl-piperidine-2,6-dione(Intermediate SV)

Step1—3-(4-Bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-methyl-piperidine-2,6-dione

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (4.00g, 11.8 mmol, Intermediate HP) and 4Å molecular sieves (300 mg) in DMF(40 mL) was added MeI (1.68 g, 11.8 mmol) and K2CO3 (1.63 g, 11.8 mmol).The reaction mixture was stirred at 25° C. for 12 hrs. On completion,the mixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel chromatography to give the titlecompound (3.70 g, 89% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6)δ 7.24 (d, J=8.0 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.00-6.94 (m, 1H),5.46 (dd, J=5.2, 12.8 Hz, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 3.00-2.90 (m,1H), 2.83-2.66 (m, 2H), 2.08-1.97 (m, 1H).

Step 2—Tert-ButylN-[2-[2-[3-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate

A mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-methyl-piperidine-2,6-dione(800 mg, 2.27 mmol), tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (1.38 g, 5.68 mmol,synthesized via Step 1 of Intermediate CQ), Pd(PPh₃)₂Cl₂ (319 mg, 454umol), CuI (86.5 mg, 454 umol), Cs₂CO₃ (3.70 g, 11.4 mmol), and 4Åmolecular sieve (800 mg) in DMF (40 mL) was de-gassed and then heated at80° C. for 2 hrs under N₂. On completion, the mixture was filtered andthe filtrate was concentrated in vacuo. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (650 mg,45% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.18 (d, J=7.6Hz, 1H), 7.13 (d, J=7.2 Hz, 1), 7.05-6.98 (m, 1), 6.82-6.75 (m, 1),5.51-5.43 (m, 1), 4.46 (s, 2H), 3.67-3.64 (m, 2H), 3.64 (s, 3H),3.57-3.54 (m, 2H), 3.47-3.42 (m, 2H), 3.10-3.06 (m, 2H), 3.03 (s, 3H),2.99-2.90 (m, 1H), 2.79-2.63 (m, 2H), 2.06-1.92 (m, 1H), 1.36 (s, 9H);LC-MS (ESI⁺) m/z 537.3 (M+Na)⁺.

Step 3—Tert-butylN-[2-[2-[3-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate(1.30 g, 2.02 mmol) in THF (20 mL) was added Pd/C (300 mg, 10% wt) andPd(OH)₂/C (300 mg, 10% wt). The reaction mixture was stirred at 25° C.for 10 hrs under H₂ (15 psi) atmosphere. On completion, the mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (1.30 g, 99% yield) as a yellow solid. LC-MS (ESI⁺) m/z 541.3(M+Na)⁺.

Step4—3-[4-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]-1-methyl-piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[3-methyl-1-(1-methyl-2,6-dioxo-3-piperidyl)-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]carbamate(1.20 g, 1.85 mmol) in DCM (10 mL) was added HCl/dioxane (10 mL). Thereaction mixture was stirred at 25° C. for 2 hrs. On completion, themixture was concentrated in vacuo to give the title compound (1.10 g,98% yield, HCl salt) as a yellow solid. LC-MS (ESI⁺) m/z 419.2 (M+H)+

Tertbutyl N-methyl-N-[3-(2-piperazin-1-ylethoxy)cyclobutyl]carbamate(Intermediate SW)

Step 1—Ethyl 2-[3-[tert-butoxycarbonyl(methyl)amino]cyclobutoxy]acetate

To a solution of ethyl2-[3-(tert-butoxycarbonylamino)cyclobutoxy]acetate (5.00 g, 18 mmol,synthesized via Step 1 of Intermediate SJ) in DMF (50 mL) at 0° C. wasadded NaH (1.50 g, 36 mmol, 60% oil dispersion) and stirred at 0° C. for0.5 hour. Then a solution of CH₃I (3.10 g, 22 mmol) in DMF (5 mL) wasadded to the reaction mixture and stirred at 0° C. for 1 hour. Oncompletion, the reaction mixture was quenched by H₂O (20 mL) at 0° C.,and then extracted with ethyl acetate (2×20 mL). The combined organiclayers were washed with brine (2×25 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (5.00 g, 95% yield) asyellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.66-4.59 (m, 1H), 4.29-4.00 (m,5H), 2.73 (s, 3H), 2.33-2.28 (m, 2H), 2.15-2.07 (m, 2H), 1.38 (s, 9H),1.22-1.16 (m, 3H).

Step 2—Tert-butyl N-[3-(2-hydroxyethoxy)cyclobutyl]-N-methyl-carbamate

To a solution of ethyl2-[3-[tert-butoxycarbonyl(methyl)amino]cyclobutoxy]acetate (2.50 g, 8.7mmol) in THF (30 mL) was added LiBH₄ (0.57 g, 26 mmol) at 0° C., thenthe reaction mixture was stirred at 25° C. for 2 hour. On completion,the reaction mixture was quenched by water (20 mL) at 25° C., and thenextracted with ethyl acetate (2×30 mL). The combined organic layers werewashed with brine (2×40 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (2.00 g, 93% yield) ascolorless oil.

Step 3—2-[3-[Tert-butoxycarbonyl(methyl)amino]cyclobutoxy]ethylmethanesulfonate

To a solution of tert-butylN-[3-(2-hydroxyethoxy)cyclobutyl]-N-methyl-carbamate (2.00 g, 8.20 mmol)and Et₃N (1.7 g, 16 mmol) in DCM (20 mL) was added MsCl (1.40 g, 12mmol), then the reaction mixture was stirred at 0° C. for 1 hour. Oncompletion, the reaction mixture was quenched by water (25 mL) at 25°C., and extracted with DCM (2×30 mL). The combined organic layers werewashed with brine (2×40 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (2.50 g, 94% yield) ascolorless oil.

Step 4—Benzyl4-[2-[3-[tert-butoxycarbonyl(methyl)amino]cyclobutoxy]ethyl]piperazine-1-carboxylate

To a solution of2-[3-[tert-butoxycarbonyl(methyl)amino]cyclobutoxy]ethylmethanesulfonate (2.50 g, 7.70 mmol) and benzyl piperazine-1-carboxylate(3.40 g, 15.0 mmol) in ACN (30 mL) was added Et₃N (2.4 g) and KI (1.50g, 9.3 mmol), then the reaction mixture was stirred at 70° C. for 12hours. On completion, the reaction mixture was filtered and concentratedin vacuo. The crude product was purified by reverse phase HPLC (0.1% FAcondition) to give the title compound (0.60 g, 16% yield) as a whitesolid. LC-MS (ESI⁺) m/z 448.1 (M+H)⁺.

Step 5—TertbutylN-methyl-N-[3-(2-piperazin-1-ylethoxy)cyclobutyl]carbamate

To a solution of benzyl4-[2-[3-[tert-butoxycarbonyl(methyl)amino]cyclobutoxy]ethyl]piperazine-1-carboxylate(0.60 g, 1.3 mmol) in MeOH (5 mL) was added Pd/C (60 mg, 10% wt), thenthe mixture was degassed and purged with H₂ gas three times. The mixturewas stirred at 25° C. for 2 hours under H₂ atmosphere. On completion,the reaction mixture was filtered and concentrated in vacuo to give thetitle compound (0.40 g, 95% yield) as colorless oil.

3-[3-Methyl-5-[[4-[2-[3-(methylamino)cyclobutoxy]ethyl]piperazin-1-yl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate SX)

Step 1—Tert-butylN-[3-[2-[4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]piperazin-1-yl]ethoxy]cyclobutyl]-N-methyl-carbamate

To a solution of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde(0.15 g, 0.52 mmol, Intermediate SK) and tertbutylN-methyl-N-[3-(2-piperazin-1-ylethoxy)cyclobutyl]carbamate (0.16 g, 0.52mmol, Intermediate SW) in a mixed solvent of THF (2 mL) and DMF (2 mL)was added Ti(i-PrO)₄ (0.22 g, 0.78 mmol) and stirred at 50° C. for 4hour, then NaBH(OAc)₃ (0.22 g, 1.0 mmol) was added at 25° C. Thereaction mixture was stirred at 25° C. for 12 hours. On completion, themixture was concentrated in vacuo. The crude product was purified byreverse phase HPLC (0.1% TFA condition) to give the title compound (40.0mg, 8.7% yield) as colorless oil. LC-MS (ESI⁺) m/z 585.4 (M+H)⁺.

Step2—3-[3-Methyl-5-[[4-[2-[3-(methylamino)cyclobutoxy]ethyl]piperazin-1-yl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[2-[4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]piperazin-1-yl]ethoxy]cyclobutyl]-N-methyl-carbamate (30.0 mg,51.3 umol) in TFA (1.5 mL) was added DCM (2 mL). The reaction mixturewas stirred at 25° C. for 2 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (30.7 mg, 100% yield)as yellow oil. LC-MS (ESI⁺) m/z 485.3 (M+H)⁺.

Tert-Butyl N-(4-but-3-ynoxybutyl)carbamate (Intermediate SY)

Step 1—1-bromo-4-but-3-ynoxy-butane

A mixture of but-3-yn-1-ol (40 g, 571 mmol, 43.2 mL, CAS #927-74-2),1,4-dibromobutane (185 g, 856 mmol, 103 mL, CAS #110-52-1), Cs₂CO₃ (204g, 627 mmol) in acetone (500 mL) was degassed and purged with N₂ for 3times. Then the mixture was stirred at 70° C. for 72 hrs under N₂atmosphere. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (40.0 g, 34% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.57 (t, J=6.8 Hz, 2H), 3.52(t, J=6.2 Hz, 2H), 3.49-3.45 (m, 3H), 2.48 (dt, J=2.8, 6.8 Hz, 2H),2.08-2.04 (m, 1H), 2.03-1.96 (m, 2H), 1.80-1.71 (m, 2H).

Step 2—2-(4-But-3-ynoxybutyl)isoindoline-1,3-dione

To a solution of 1-bromo-4-but-3-ynoxy-butane (27.0 g, 131 mmol) in DMF(300 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (29.3 g, 158mmol). The mixture was stirred at 60° C. for 6 hrs. On completion, 1500mL H₂O was added to the mixture, and the mixture was extracted with EA(2×800 mL). The organic layer was washed with brine (300 mL), and thenconcentrated in vacuo to give the title compound (30.0 g, 84% yield) aswhite solid. ¹H NMR (400 MHz, CDCl₃) δ 7.87-7.83 (m, 2H), 7.75-7.70 (m,2H), 3.73 (t, J=7.2 Hz, 2H), 3.53 (td, J=6.8, 19.2 Hz, 4H), 2.45 (dt,J=2.8, 7.2 Hz, 2H), 1.98 (t, J=2.8 Hz, 1H), 1.83-1.71 (m, 2H), 1.69-1.59(m, 2H).

Step 3—4-But-3-ynoxybutan-1-amine

To a solution of 2-(4-but-3-ynoxybutyl)isoindoline-1,3-dione (50.0 g,184 mmol) in EtOH (1000 mL) was added NH₂NH₂H₂O (92.3 g, 1.84 mol, 89.6mL). The mixture was stirred at 80° C. for 4 hrs. On completion, themixture was filtered and the filtrate was concentrated in vacuo to givethe title compound (21.0 g, 31% yield) as colorless oil. ¹H NMR (400MHz, CDCl₃) δ 3.49 (t, J=7.2 Hz, 2H), 3.43-3.38 (m, 2H), 2.65 (t, J=7.2Hz, 2H), 2.39 (dt, J=2.8, 6.8 Hz, 2H), 1.91 (t, J=2.8 Hz, 1H), 1.89 (s,2H), 1.60-1.52 (m, 2H), 1.49-1.40 (m, 2H).

Step 4—Tert-butyl N-(4-but-3-ynoxybutyl)carbamate

To a solution of 4-but-3-ynoxybutan-1-amine (30.0 g, 212 mmol) in MeOH(300 mL) was added (Boc)₂O (69.6 g, 318 mmol, 73.2 mL). The mixture wasstirred at 25° C. for 4 hrs. On completion, the mixture was concentratedin vacuo. The residue was purified by silica gel chromatography to givethe title compound (50.0 g, 97% yield) as colorless oil. ¹H NMR (400MHz, CDCl₃) δ 4.68 (s, 1H), 3.57 (t, J=6.8 Hz, 2H), 3.49 (t, J=6.0 Hz,2H), 3.20-3.11 (m, 2H), 2.48 (dt, J=2.8, 6.8 Hz, 2H), 1.99 (t, J=2.8 Hz,1H), 1.68-1.59 (m, 4H), 1.46 (s, 9H).

3-[3-methyl-5-[3-[(2R)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate SZ)

Step1—3-[5-[3-[(2R)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of1-(4-methoxyphenyl)-N-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]methanamine (900 mg, 3.12 mmol, Intermediate TO) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (703mg, 2.08 mmol, Intermediate HN) in DMF (20 mL) was added 4Å molecularsieves (300 mg), Pd(PPh₃)₂Cl₂ (146 mg, 208 umol), Cs₂CO₃ (2.71 g, 8.32mmol) and CuI (39.6 mg, 208 umol). The reaction mixture was stirred at80° C. for 2 hr under N₂. On completion, the mixture was filtered, andthe filtrate was concentrated in vacuo to give a residue. The residuewas purified by reverse phase (0.1% FA condition) to give the titlecompound (1.10 g, 96% yield) as a yellow solid. LC-MS (ESI⁺) m/z 546.4(M+H)⁺.

Step 2—Tert-ButylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of3-[5-[3-[(2R)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (500mg, 916 umol) in IPA (15 mL) and EA (30 mL) was added Pd(OH)₂/C (200 mg,10 wt %), Pd/C (200 mg, 10 wt %) and (Boc)₂O (300 mg, 1.37 mmol, 315uL). The reaction mixture was stirred at 25° C. for 48 hr under H₂ (50psi). On completion, the residue was filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.10% FA condition) to give the title compound (300 mg,62% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.08-6.93 (m, 2H), 6.86 (d, J=8.0 Hz, 1), 5.75 (s, 1), 5.33 (dd, J=5.2,12.8 Hz, 1H), 3.63-3.56 (m, 4H), 3.52-3.46 (m, 2H), 3.31 (s, 3H),3.26-3.12 (m, 3H), 2.93-2.85 (m, 1H), 2.72-2.58 (m, 6H), 2.07-1.96 (m,2H), 1.81-1.69 (m, 3H), 1.37 (s, 9H); LC-MS (ESI⁺) m/z 530.3 (M+H)⁺.

Step3—3-[3-Methyl-5-[3-[(2R)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate (300 mg, 566 umol) inDCM (8 mL) was added HCl/dioxane (4 M, 4 mL). The reaction mixture wasstirred at 25° C. for 2 hr. On completion, the mixture was concentratedin vacuo to give the title compound (260 mg, 98% yield, HCl) as a whitesolid. LC-MS (ESI⁺) m/z 430.2 (M+H)⁺.

Tert-Butyl4-[3-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(Intermediate TA)

Step 1—Tert-butyl4-[3-[[3-(difluoromethyl)-1-(4-methoxycarbonylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate

To a solution of methyl4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate (650 mg, 2.43 mmol,Intermediate FW),5-(4-tertbutoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (650 mg, 1.87 mmol, Intermediate RC) in ACN (15.0 mL) was addedDIPEA (725 mg, 5.61 mmol), HATU (1.42 g, 3.74 mmol). The mixture wasstirred at 60° C. for 16 hrs. On completion, the mixture wasconcentrated in vacuo. The mixture was purified by reverse phase: (0.10%FA) to give the title compound (700 mg, 62% yield) as yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.48 (s, 1H), 8.38(d, J=8.0 Hz, 1H), 8.17 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H),7.09-6.76 (m, 1H), 6.46 (d, J=8.0 Hz, 1H), 3.96 (s, 3H), 3.86 (s, 4H),3.65 (s, 4H), 1.54 (s, 9H).

Step2—4-[4-[[5-(4-Tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicAcid

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-(4-methoxycarbonylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (1.00g, 1.68 mmol) in THF (40.0 mL) and H₂O (8 mL) was added LiOH (200 mg,8.38 mmol). The mixture was stirred at 20° C. for 16 hrs. On completion,the mixture was concentrated in vacuo. The mixture was diluted with H₂O(30 mL), then the mixture was acidified with 1N HCl solution until thepH=5. The mixture was filtered and the filter cake was dried in vauco togive the title compound (900 mg, 92% yield) as yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 12.01 (s, 1H), 9.48 (s, 1H), 9.08 (s, 1H), 8.82 (d,J=8.0 Hz, 1H), 8.32 (s, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz,2H), 7.52-7.16 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 3.82 (s, 4H), 3.50 (s,4H), 1.44 (s, 9H).

Step 3—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-(4-isopropoxycarbonyloxycarbonylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]-1-carboxylate

To a solution of4-[4-[[5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoic acid (900 mg, 1.54 mmol),TEA (625 mg, 6.18 mmol) in THF (30.0 mL) was added isopropylcarbonochloridate (473 mg, 3.86 mmol) at −10° C. The mixture was stirredat −10° C. for 1 hrs. On completion, the mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (1.00 g,90% yield) as yellow solid. LC-MS (ESI⁺) m/z 669.2 (M+H)⁺.

Step 4—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-(4-isopropoxycarbonyloxycarbonylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(1.00 g, 1.50 mmol) in THF (50.0 mL) and H₂O (10.0 mL) was added LiBH₄(195 mg, 8.97 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr.On completion, the mixture was quenched with H₂O (10 mL), then extractedwith DCM (2×30 mL). The organic layers were dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo. The mixture was triturated with DCM(5 mL) to give the title compound (700 mg, 82% yield) as yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.98 (s, 1), 8.85 (d, J=8.0Hz, 1), 8.33 (s, 1), 7.80 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H),7.34-6.96 (m, 1), 6.91 (d, J=8.0 Hz, 1), 5.35-5.24 (m, 1), 4.56 (d,J=4.4 Hz, 2H), 3.84 (s, 4H), 3.50 (s, 4H), 1.45 (s, 9H).

Step 5—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-(4-formylphenvl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (700mg, 1.23 mmol) in THF (30.0 mL) was added DMP (626 mg, 1.48 mmol). Themixture was stirred at 20° C. for 1 hr. On completion, the mixture wasquenched with saturated Na₂S₂O₃ (30 mL) and washed with saturated NaHCO₃(2×30 mL). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (680 mg, 90% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.52 (s, 1),9.17 (s, 1), 8.86 (d, J=8.0 Hz, 1), 8.35 (s, 1), 8.15-8.10 (m, 2H),8.09-8.03 (m, 2H), 7.54-7.23 (m, 1H), 6.96-6.86 (m, 1H), 3.85 (s, 4H),3.51 (s, 4H), 1.45 (s, 9H).

2-[(E)-2-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]vinyloxy]ethylmethanesulfonate (Intermediate TB)

Step1—3-[5-[(E)-2-(2-Hydroxyethoxy)vinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00g, 2.96 mmol, Intermediate HN), 2-vinyloxyethanol (782 mg, 8.88 mmol,CAS #764-48-7) in dioxane (25 mL) was added P(t-Bu)₃ toluene solution(2.08 mL, 591 umol, 10 wt %), Pd₂(dba)₃ (542 mg, 591 umol) and DIPEA(497 mg, 3.84 mmol) under N₂. The mixture was stirred at 25° C. for 16hours. On completion, the mixture was concentrated in vacuo. The residuewas purified by silica gel column to give the title compound (500 mg,49% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.25-7.19 (m, 1), 7.19-7.09 (m, 1H), 6.99 (d, J=8.4 Hz, 1), 6.95-6.90(m, 1H), 6.35 (d, J=7.2 Hz, 1H), 5.88 (d, J=12.8 Hz, 1H), 5.38-5.29 (m,1H), 5.25 (d, J=7.2 Hz, 1H), 3.99-3.83 (m, 1H), 3.85 (t, J=5.2 Hz, 1H),3.69-3.61 (m, 2H), 3.39 (s, 3H), 2.97-2.82 (m, 1), 2.66-2.58 (m, 1),2.53 (d, J=1.6 Hz, 1H), 2.06-1.99 (m, 1H).

Step2—2-[(E)-2-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]vinyloxy]ethylmethanesulfonate

To a solution of3-[5-[(E)-2-(2-hydroxyethoxy)vinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(750 mg, 2.17 mmol) in DCM (100 mL) was added TEA (659 mg, 6.52 mmol)and MsCl (373 mg, 3.26 mmol) at 0° C. The reaction mixture was stirredat 25° C. for 2 hours. On completion, the reaction mixture was pouredinto water (30 mL) and extracted with DCM (2×100 mL). The combinedorganic layers were washed with brine (80 mL) and sat. aq. NaHCO₃ (2×70mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo togive the title compound (800 mg, 70% yield, 75% purity) as a brownsolid. LC-MS (ESI⁺) m/z 423.9 (M+H)⁺.

3-[5-[2-[2-[(2S)-2-(Aminomethyl)morpholin-4-yl]ethoxy]ethyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate TC)

Step1—Tert-butylN-[[(2S)-4-[2-[(E)-2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]vinyloxy]ethyl]morpholin-2-yl]methyl]carbamate

To a solution of2-[(E)-2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]vinyloxy]ethylmethanesulfonate (350 mg, 827 umol, Intermediate TB), tert-butylN-[[(2R)-morpholin-2-yl]methyl]carbamate (268 mg, 1.24 mmol, CAS#186202-57-3) in DMF (5 mL) was added DIPEA (320 mg, 2.48 mmol) at 20°C. The mixture was stirred at 110° C. for 1 hour. On completion, themixture was concentrated in vacuo. The mixture was purified by prep-HPLC(reverse phase: 0.1% FA) to give the title compound (270 mg, 60% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 6.97-6.82 (m,2H), 6.82-6.69 (m, 1), 6.12 (d, J=7.2 Hz, 1), 5.95 (d, J=12.8 Hz, 1H),5.43 (d, J=7.1 Hz, 1H), 5.26-5.18 (m, 1H), 4.89 (s, 1H), 4.39-4.18 (m,2H), 4.06 (d, J=7.2 Hz, 2H), 3.98-3.87 (m, 1H), 3.68-3.54 (m, 2H),3.46-3.43 (m, 3H), 3.41-3.36 (m, 2H), 3.33-3.24 (m, 2H), 2.99-2.91 (m,2H), 2.87-2.81 (m, 1), 2.79-2.75 (m, 1), 2.74-2.68 (m, 1), 2.31-2.21 (m,1), 1.47 (s, 9H).

Step 2—Tert-butylN-[[(2S)-4-[2-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-[[(2S)-4-[2-[(E)-2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]vinyloxy]ethyl]morpholin-2-yl]methyl]carbamate(270 mg, 496 umol) in THF (20 mL) was added Pd/C (50.0 mg, 10 wt %) andPd(OH)₂/C (50.0 mg, 10 wt %) at 25° C. The mixture was stirred at 25° C.for 2 hours under H₂ (15 psi). On completion, the mixture was filtered.The filtrate was concentrated in vacuo. The mixture was purified byprep-HPLC (reverse phase: 0.10% FA) to give the title compound (150 mg,30% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H),7.09 (s, 1H), 7.04-6.94 (m, 2H), 6.65 (s, 1H), 5.37-5.33 (m, 1H), 3.68(s, 3H), 3.65-3.59 (m, 4H), 3.34 (s, 3H), 3.04-2.93 (m, 4H), 2.91-2.79(m, 4H), 2.75-2.70 (m, 1), 2.66-2.61 (m, 1), 2.55-2.53 (m, 1), 2.04-1.96(m, 1H), 1.78-1.75 (m, 2H), 1.36 (s, 9H).

Step3—3-[5-[2-[2-[(2S)-2-(Aminomethyl)morpholin-4-yl]ethoxy]ethyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[2-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]ethoxy]ethyl]morpholin-2-yl]methyl]carbamate(100 mg, 184 umol) in DCM (2 mL) was added TFA (1 mL) at 15° C. Themixture was stirred at 15° C. for 2 hours. On completion, the mixturewas concentrated in vacuo to give the title compound (80.0 mg, 98%yield, TFA salt) as a white solid. LC-MS (ESI⁺) m/z 446.3 (M+H)⁺.

3-[6-[3-[2-[2-(Methylamino)ethoxy]ethoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate TF)

Step 1—Tert-ButylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]-2-ynoxy]ethoxy]ethyl]-N-methyl-carbamate

A mixture of tert-butylN-methyl-N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (427 mg, 1.66 mmol,Intermediate FY),3-(6-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (300 mg, 923umol, Intermediate OZ), 4Å molecular sieves (40 mg), Pd(PPh₃)₂Cl₂ (129mg, 185 umol), CuI (35.2 mg, 184 umol) and Cs₂CO₃ (1.50 g, 4.61 mmol) inDMF (10 mL) was de-gassed and then heated at 80° C. for 2 hrs. Oncompletion, the reaction mixture was concentrated in vacuo. The crudeproduct was purified by reversed-phase HPLC (0.1% FA condition) to givethe title compound (280 mg, 610% yield) as yellow oil. LC-MS (ESI⁺) m/z524.3 (M+Na)⁺.

Step 2—Tert-butylN-[2-[2-[3-[3(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]ethoxy]thyl]-N-methyl-carbamate

To a solution oftert-butyl-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-xo-1,3-benzoxazol-6-1]prop-2-noxy]ethoxyethyl]-N-methyl-carbamate(280 mg, 558 umol) in THF (20 mL) was added Pd/C (50 mg, 10% wt) andPd(OH)₂/C (50 mg, 10% wt) under N₂ atmosphere. The suspension wasdegassed under vacuum and purged with H₂ several times. The reactionmixture was stirred at 25° C. for 4 hrs under H₂ (15psi). On completion,the reaction mixture was filtered and the filtrate was concentrated invacuo to give the title compound (150 mg, 53% yield) as yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ 11.19 (s, 1H), 7.25-7.23 (m, 1H), 7.15-7.11 (m,1H), 7.03 (d, J=7.6 Hz, 1H), 5.34 (dd, J=5.2, 12 Hz, 1H), 3.5-3.48 (m,4H), 3.42-3.39 (m, 2H), 3.37-3.35 (m, 3H), 3.31-3.27 (m, 4H), 2.81-2.80(m, 2H), 2.69-2.61 (m, 1H), 2.63-2.61 (m, 2H), 2.13-2.10 (m, 1H),1.80-1.75 (m, 2H), 1.37 (s, 9H); LC-MS (ESI⁺) m/z 528.3 (M+Na)⁺.

Step3—3-[6-[3-[2-[2-(Methylamino)ethoxy]ethoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]ethoxy]ethyl]-N-methyl-carbamate (140 mg, 277 umol) in DCM (3 mL) wasadded TFA (2 mL). The mixture was stirred at 25° C. for 2 hrs under N₂atmosphere. On completion, the reaction mixture was concentrated invacuo to give the title compound (11.9 mg, 39% yield) as white solid.LC-MS (ESI⁺) m/z 406.2 (M+H)⁺.

3-[6-[3-[3-(Methylamino)propoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(Intermediate TH)

Step 1—Tert-Butyl(3-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)prop-2-yn-1-yl)oxy)propyl)(methyl)carbamate

A mixture of 3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(100 mg, 0.279 mmol, Intermediate UH), tert-butylmethyl(3-(prop-2-yn-1-yloxy)propyl)carbamate (190 mg, 0.838 mmol,Intermediate UI), Pd(PPh₃)₂Cl₂ (30 mg, 0.0419 mmol), CuI (4 mg, 0.0223mmol), Cs₂CO₃ (455 mg, 1.40 mmol), 4Å MS (200 mg) and DMF (5 mL) washeated to 80° C. under microwave for 1.5 h under N₂. The mixture wasthen poured into 1N HCl (20 mL), then extracted with EA (3×20 mL). Theorganic layers were washed with brine (20 mL), dried over Na₂SO₄,filtered, concentrated and purified by column chromatography on silicagel (PE/EA=10/1 to 5/1 to 2/1) to give the title compound (50 mg, 35%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J=7.2 Hz,1H), 8.46 (dd, J=1.2 Hz, J=5.6 Hz, 11H), 8.25 (d, J=1.2 Hz, 1H), 8.13(s, 1H), 7.65 (dd, J=1.6 Hz, J=4.0 Hz, 1H), 7.25-7.19 (m, 2H), 5.90 (dd,J=2.8 Hz, J=6.0 Hz, 1), 4.41 (s, 2H), 3.63 (t, J=6.4 Hz, 2H), 3.34 (t,J=7.2 Hz, 2H), 3.02-2.91 (m, 3H), 2.89 (s, 3H), 2.50-2.47 (m, 1H), 1.88(t, J=6.8 Hz, 2H), 1.46 (s, 9H). LC/MS (ESI, m/z): [M+1]⁺=505.2.

Step 2—Tert-Butyl(3-(3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)propoxy)propyl)(methyl)carbamate

A mixture of tert-butyl(3-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)prop-2-yn-1-yl)oxy)propyl)(methyl)carbamate(320 mg, 0.634 mmol), Pd/C (320 mg) and EA (10 mL) was stirred forovernight at rt under H₂. The mixture was filtered, concentrated andpurified by column (PE/EA=1/1) to give the title product (170 mg, 53%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (dd, J=1.6 Hz,J=4.8 Hz, 1H), 8.32 (d, J=7.6 Hz, 1H), 8.15 (s, 1H), 7.91 (d, J=0.8 Hz,1H), 7.33 (dd, J=1.2 Hz, J=8.0 Hz, 1), 7.22-7.16 (m, 2H), 5.94 (br s,1), 3.45 (dd, J=6.4 Hz, J=11.6 Hz, 4H), 3.13 (t, J=5.8 Hz, 2H),3.07-2.95 (m, 3H), 2.88-2.84 (m, 5H), 2.33-2.29 (m, 1H), 2.01-1.93 (m,2H), 1.85-1.78 (m, 2H), 1.46 (s, 9H). LC/MS (ESI, m/z): [M−BOC+H]⁺=409.2and [M−56+H]⁺=453.2.

Step3—3-[6-[3-[3-(Methylamino)propoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]propoxy]propyl]-N-methyl-carbamate(85.0 mg, 167 umol) in DCM (6 mL) was added TFA (381 mg, 3.34 mmol). Themixture was stirred at 25° C. for 2 hrs. On completion, the reactionmixture was concentrated in vacuo to give the title compound (87 mg, 95%yield, TFA salt) as light yellow oil. LC-MS (ESI⁺) m/z 409.3 (M+H)⁺.

2-(2-Prop-2-ynoxyethoxy)ethyl 4-methylbenzenesulfonate (Intermediate TI)

To a solution of 2-(2-prop-2-ynoxyethoxy)ethanol (2.00 g, 13.8 mmol,Intermediate LC), TEA (4.21 g, 41.6 mmol) and DMAP (170 mg, 1.39 mmol)in DCM (60 mL) was added 4-methylbenzenesulfonyl chloride (5.29 g, 27.7mmol) at 0° C. The mixture was then stirred at 25° C. for 16 hours. Oncompletion, the mixture was washed with 2.0 M aq.HCl (20 mL) and brine(20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel to give thetitle compound (3.40 g, 82% yield) as light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.81 (d, J=8.4 Hz, 2H), 7.35 (m, J=8.0 Hz, 2H), 4.23-4.14 (m,4H), 3.73-3.68 (m, 2H), 3.67-3.59 (m, 4H), 2.46 (s, 3H), 2.44 (t, J=2.4Hz, 1H).

N-[6-(1-hydroxy-1-methyl-ethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate TJ)

Step 1—Methyl 5-nitro-1H-indazole-6-carboxylate

To a solution of methyl 1H-indazole-6-carboxylate (10.0 g, 56.7 mmol) inH₂SO₄ (100 mL) was added a solution of HNO₃ (12.1 g, 125 mmol, 65%purity) in H₂SO₄ (20 mL) at −10-0° C. during 30 minutes. The mixture wasstirred at −10-0° C. for 1 hour. On completion, the mixture was pouredinto ice/water (1.0 L) slowly. The mixture was filtered and the filtercake was washed with water (2×200 mL). Then the cake was collected anddried in vacuo to give the title compound (11.9 g, 94% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.44 (s, 1H), 7.97 (s,1H), 3.86 (s, 3H).

Step 2—Methyl 5-amino-1H-indazole-6-carboxylate

To a solution of methyl 5-nitro-1H-indazole-6-carboxylate (10.9 g, 49.2mmol) in MeOH (100 mL) and THF (60 mL) was added a solution of NH₄Cl(26.3 g, 492 mmol) in H₂O (100 mL) at 25° C. Then Fe (13.7 g, 245 mmol)was added to the mixture in portions at 70° C., and the mixture wasstirred at 70° C. for 1 hour. On completion, the mixture was filteredand the filter cake was washed with EA (200 mL). The filtrate wasconcentrated in vacuo. The residue was washed with water (100 mL), andextracted with EA (3×100 mL). The combined organic layer was washed withbrine (100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo tothe title compound (7.30 g, 77% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 12.82 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 6.99 (s, 1H), 6.00(s, 2H), 3.85 (s, 3H).

Step 3—Methyl5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1H-indazole-6-carboxylate

To a solution of methyl 5-amino-1H-indazole-6-carboxylate (7.20 g, 37.6mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (6.48 g, 33.9 mmol,CAS #131747-42-7) and DIPEA (7.35 g, 56.8 mmol) in THF (70 mL) was addedT₃P (47.9 g, 44.8 mL, 50 wt %) slowly at 0° C. Then the mixture wasstirred at 0-5° C. for 2 hours. On completion, the reaction was quenchedwith cold water (0.1 mL). The mixture was diluted with water (280 mL),and stirred at 25° C. for 0.5 hour. The mixture was filtered and thefilter cake was washed with water (30 mL). The filter cake was collectedand dried in vacuo to give the title compound (12.3 g, 99% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (s, 1H), 9.15 (s, 1H),8.47 (d, J=7.6 Hz, 1H), 8.39 (t, J=7.6 Hz, 1H), 8.30 (s, 1H), 8.25 (s,1H), 8.20 (d, J=8.0 Hz, 1H), 3.97 (s, 3H).

Step4—N-[6-(1-hydroxy-1-methyl-ethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide

To a solution of methyl5-[[6-(trifluoromethyl)pyridine-2-carbonyl]amino]-1H-indazole-6-carboxylate(4.00 g, 10.9 mmol) in THF (40 mL) was added MeMgBr-Et₂O solution (3.0M, 29.3 mL) slowly at 0° C. The mixture was stirred at 0-25° C. for 16hours. On completion, the reaction was quenched with sat.NH₄Cl (40 mL)slowly at 0-10° C. The mixture was extracted with EA (3×40 mL). Thecombined organic layer was concentrated in vacuo. The residue waspurified by reverse phase chromatography (FA condition) to give thetitle compound (1.50 g, 37% yield) as light yellow solid. ¹H NMR (400MHz, CDCl₃) δ 12.23 (s, 1H), 8.96 (s, 1H), 8.52 (d, J=7.6 Hz, 1H), 8.12(t, J=7.6 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.50 (s, 1H),1.80 (s, 6H).

N-[6-(1-hydroxy-1-methyl-ethyl)-2-[2-(2-prop-2-ynoxyethoxy)ethyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(Intermediate TK)

To a solution ofN-[6-(1-hydroxy-1-methyl-ethyl)-2H-indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(300 mg, 823 umol, Intermediate TJ) and DIPEA (532 mg, 4.12 mmol) intoluene (10 mL) was added a solution of 2-(2-prop-2-ynoxyethoxy)ethyl4-methylbenzenesulfonate (983 mg, 3.29 mmol, Intermediate TI) in toluene(5 mL) at 110° C. during 1 hour. Then, the mixture was stirred at 110°C. for 35 hours. On completion, after cooled to 25° C., the mixture wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel to give the title compound (130 mg, 32% yield) as lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 12.26 (s, 1H), 8.83 (s, 1H), 8.47(d, J=8.0 Hz, 1), 8.08 (t, J=8.0 Hz, 1), 8.00 (s, 1), 7.82 (m, J=7.6 Hz,1H), 7.67 (s, 1H), 4.57 (t, J=5.2 Hz, 2H), 4.16 (d, J=2.4 Hz, 2H), 3.97(t, J=5.2 Hz, 2H), 3.66-3.58 (m, 4H), 2.47 (t, J=2.4 Hz, 1), 1.79 (s,6H).

3-[6-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(Intermediate TL)

Step 1—Tert-Butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

A mixture of 3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(600 mg, 1.68 mmol, Intermediate UH), tert-butyl(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (1.2 g, 5.03 mmol,Intermediate IT), Pd(PPh₃)₂Cl₂ (179 mg, 0.252 mmol), CuI (26 mg, 0.134mmol), Cs₂CO₃ (55 g, 16.8 mmol), 4Å MS (1 g) and DMF (10 mL) was heatedto 80° C. under microwave for 1.5 h under N₂. The mixture was thenpoured into 1N HCl (400 mL), and extracted with EA (100 mL). The organiclayer was washed with brine (30 mL), dried over Na₂SO₄, filtered,concentrated and purified by column (PE/EA=10/1 to 5/1 to 2/1) to givethe title compound (250 mg, 29% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.45 (dd, J=1.2 Hz, J=4.8 Hz, 1H), 8.34 (dd, J=1.2 Hz,J=7.6 Hz, 1H), 8.21 (d, J=0.8 Hz, 1H), 8.15 (s, 1H), 7.59 (dd, J=1.2 Hz,J=8.4 Hz, 1), 7.27-7.22 (m, 2H), 5.95 (br s, 1), 5.01 (br s, 1H), 4.47(s, 2H), 3.81-3.79 (m, 2H), 3.71-3.69 (m, 2H), 3.58 (t, J=5.2 Hz, 2H),3.33-3.34 (m, 2H), 3.09-2.96 (m, 2H), 2.35-2.31 (m, 1H), 2.02-1.99 (m,1H), 1.44 (s, 9H). LC/MS (ESI, m/z): [M−Boc+1]⁺=421.3.

Step 2—Tert-Butyl(2-(2-(3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)propoxy)ethoxy)ethyl)carbamate

A mixture of tert-butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-6-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(250 mg, 0.481 mmol), Pd/C (100 mg) and EA (15 mL) was stirred forovernight at rt under H₂. The mixture was filtered, concentrated andpurified by column (PE/EA=1/1) to give the title compound (150 mg, 60%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (dd, J=1.2 Hz,J=4.8 Hz, 1H), 8.31 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 8.22 (s, 1H), 7.92 (d,J=0.8 Hz, 1H), 7.33 (dd, J=1.6 Hz, J=8.4 Hz, 1H), 7.21-7.16 (m, 2H),5.92-5.88 (m, 1H), 5.04 (br s, 1H), 3.64-3.50 (m, 8H), 3.33 (d, J=4.8Hz, 2H), 3.08-2.85 (m, 5H), 2.32-2.28 (m, 1H), 2.04-1.97 (m, 2H), 1.43(s, 9H); LC/MS (ESI, m/z): [M−Boc+1]⁺=425.2.

Step3—3-[6-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-6-yl]propoxy]ethoxy]ethyl]carbamate (54.0 mg, 102 umol) in DCM (3 mL) was added TFA(352 mg, 3.09 mmol). The mixture was stirred at 25° C. for 1 hr. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (55.0 mg, 95% yield, TFA salt) as light yellow oil. LC-MS(ESI⁺) m/z 425.3 (M+H)⁺.

Step 1—Tert-butyl 4-prop-2-ynoxypiperidine-1-carboxylate (IntermediateTM)

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g,9.94 mmol, CAS #109384-19-2) in anhydrous THF (10 mL) was cooled to 0°C., and subsequently NaH (477 mg, 11.9 mmol, 60% oil dispersion) wasadded. The reaction mixture was stirred at 0° C. for 0.5 hr. Then,3-bromoprop-1-yne (1.18 g, 9.94 mmol, 856 uL) was added. The resultingreaction mixture was stirred at 25° C. for 12 hrs. On completed, thereaction mixture was quenched with water (1 mL), then diluted with ethylacetate (100 mL). The organic layers were washed with brine (20 mL),dried over anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyto give the title compound (2.38 g, 100% yield) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 4.22 (d, J=2.4 Hz, 2H), 3.84-3.75 (m, 2H), 3.73-3.70(m, 1H), 3.15-3.09 (m, 2H), 2.43 (t, J=2.4 Hz, 11H), 1.93-1.82 (m, 2H),1.61-1.50 (m, 2H), 1.47 (s, 9H).

3-[3-Methyl-2-oxo-4-[3-(4-piperidyloxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate TN)

Step 1—Tert-Butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate

A suspension of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300mg, 887 umol, Intermediate HP), tert-butyl4-prop-2-ynoxypiperidine-1-carboxylate (318 mg, 1.33 mmol,Intermediate™), Pd(PPh₃)₂Cl₂ (124 mg, 177 umol), CuI (33.8 mg, 177umol), 4Å molecular sieves (400 mg) and Cs₂CO₃ (1.16 g, 3.55 mmol) inDMF (5 mL) was de-gassed under vacuum and purged with N₂ several timesand then heated to 80° C. for 2 hours under N₂. On completion, thereaction mixture was concentrated in vacuo to remove DMF. The residuewas diluted with EA (50 mL) and water (20 mL). After, the organic layerwas separated and washed with brine (5 mL×2), dried over anhydrousNa₂SO₄, filtered and the filtrate was concentrated in vacuo to give aresidue. The residue was purified by reverse phase to give the titlecompound (222 mg, 48% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃)δ 8.09 (s, 1H), 7.10 (d, J=8.0 Hz, 1), 6.92 (t, J=8.0 Hz, 1), 6.69 (d,J=8.0 Hz, 1H), 5.13 (dd, J=5.2, 12.8 Hz, 1H), 4.39 (s, 2H), 3.76-3.66(m, 6H), 3.09-3.03 (m, 2H), 2.94-2.84 (m, 1H), 2.82-2.71 (m, 1H),2.71-2.59 (m, 1H), 2.22-2.11 (m, 1H), 1.83-1.78 (m, 2H), 1.57-1.49 (m,2H), 1.39 (s, 9H), LC-MS (ESI⁺) m/z 441.2 (M+H−56)⁺.

Step2—Tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]piperidine-1-carboxylate

To a solution of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate(370 mg, 745 umol) in THF (10 mL) was added Pd/C (0.1 g, 10% wt) andPd(OH)₂/C (0.1 g, 10% wt). The suspension was degassed under vacuum andpurged with H₂ several times. The mixture was stirred under H₂ (15 psi)at 25° C. for 12 hours. On completion, the reaction mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(330 mg, 88% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (s,1H), 6.91 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1), 6.59 (t, J=8.0 Hz,1), 5.20-5.09 (m, 1), 3.70-3.64 (m, 2H), 3.62 (s, 3H), 3.44 (t, J=5.6Hz, 2H), 3.41-3.34 (m, 1H), 3.06-3.04 (m, 2H), 2.98-2.93 (m, 2H),2.91-2.80 (m, 1H), 2.79-2.63 (m, 2H), 2.19-2.10 (m, 1H), 1.89-1.81 (m,2H), 1.80-1.73 (m, 2H), 1.47-1.39 (m, 2H), 1.39 (s, 9H); LC-MS (ESI⁺)m/z 523.1 (M+Na)⁺.

Step3—3-[3-Methyl-2-oxo-4-[3-(4-piperidyloxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]piperidine-1-carboxylate (100 mg, 199 umol) in DCM (4 mL) was addedHCl/dioxane (4 M, 2 mL). The reaction mixture was stirred at 25° C. for0.5 hr. On completion, the reaction mixture was concentrated in vacuo togive the title compound (87.0 mg, 100% yield, HCl salt) as a whitesolid. LC-MS (ESI⁺) m/z 401.1 (M+H)⁺.

1-(4-Methoxyphenyl)-N-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]methanamine(Intermediate TO)

Step 1—(2S)-4-prop-2-ynylmorpholine-2-carbaldehyde

To a solution of [(2S)-4-prop-2-ynylmorpholin-2-yl]methanol (5.00 g,32.2 mmol, synthesized via Steps 1-2 of Intermediate RV) in DCM (250 mL)was added DMP (17.0 g, 40.0 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 2 hrs. On completion, the reaction mixture wasquenched with saturated NaS₂O₃ (30 mL), then extracted with DCM (3×100mL). The combined organic layers was washed with saturated NaHCO₃ (50mL), then washed with brine (50 mL), dried over anhydrous sodiumsulfate, and filtered. The filtrate was concentrated in vacuo to givethe title compound (2.80 g, 56% yield) as yellow oil.

Step2—1-(4-Methoxyphenyl)-N-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]methanamine

To a solution of (2S)-4-prop-2-ynylmorpholine-2-carbaldehyde (2.80 g,18.2 mmol) and 1-(4-methoxyphenyl)-N-methylmethanamine (2.76 g, 18.2mmol, CAS #702-24-9) in DCM (50 mL) was added NaBH(OAc)₃ (4.65 g, 21.9mmol), 4Å molecular sieves (1 g) and HOAc (1.10 g, 18.2 mmol, 1.05 mL).The reaction mixture was stirred at 25° C. for 12 hrs. On completion,the reaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% NH₃H₂O condition) to givethe title compound (1.50 g, 25% yield) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.25-7.18 (m, 2H), 6.90-6.82 (m, 2H), 3.96-3.88 (m, 1H), 3.81(s, 3H), 3.78-3.73 (m, 1H), 3.73-3.65 (m, 1H), 3.56-3.44 (m, 2H), 3.31(t, J=2.4 Hz, 2H), 2.86-2.80 (m, 1H), 2.73-2.67 (m, 1H), 2.55-2.48 (m,1H), 2.41-2.33 (m, 2H), 2.27 (t, J=2.4 Hz, 1H), 2.25 (s, 3H), 2.09-2.03(m, 1H); LC-MS (ESI⁺) m/z 289.2 (M+H)⁺.

3-[(5S)-5-[4-[4-(3-aminopropoxy)but-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(Intermediate TP)

Step 1—Tert-ButylN-[3-[4-[4-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl]but-3-ynoxy]propyl]carbamate

To a solution of tert-butyl N-(3-but-3-ynoxypropyl)carbamate (250 mg,1.10 mmol, Intermediate SD) and3-[(5S)-5-(4-bromophenyl)-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione(323 mg, 916 umol, Intermediate SN) in DMF (15 mL) was addedPd(PPh₃)₂Cl₂ (64.3 mg, 91.6 umol), CuI (17.4 mg, 91.6 umol) and Cs₂CO₃(1.19 g, 3.67 mmol). The reaction mixture was stirred at 80° C. for 2hrs under N₂. On completion, the mixture was filtered, and the filtratewas concentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (250 mg,54% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR (400MHz, DMSO-d₆) δ 11.00 (m, 1H), 7.50-7.35 (m, 4H), 6.79 (t, J=5.2 Hz, 1),5.72-5.59 (m, 1H), 4.78-4.61 (m, 1H), 3.97-3.83 (m, 1H), 3.59-3.51 (m,2H), 3.44 (t, J=6.0 Hz, 2H), 3.25 (t, J=8.4 Hz, 1H), 2.99 (q, J=6.8 Hz,2H), 2.92-2.77 (m, 1H), 2.70-2.64 (m, 2H), 2.59-2.54 (m, 1), 2.29-2.14(m, 1), 2.05-1.91 (m, 1), 1.67-1.58 (m, 2H), 1.37 (s, 9H); LC-MS (ESI⁺)m/z 522.3 (M+Na)⁺.

Step2—3-[(5S)-5-[4-[4-(3-aminopropoxy)but-1-ynyl]phenyl]-2-oxo-oxazolidin-3-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[4-[4-[(5S)-3-(2,6-dioxo-3-piperidyl)-2-oxo-oxazolidin-5-yl]phenyl]but-3-ynoxy]propyl]carbamate (100 mg, 200 umol) in DCM (3 mL) was addedTFA (1.54 g, 13.5 mmol, 1.00 mL). The reaction mixture was stirred at25° C. for 2 hr. On completion, the residue concentrated in vacuo togive the title compound (100 mg, 97% yield) as yellow oil. LC-MS (ESI⁺)m/z 400.2 (M+H)⁺.

3-[3-Methyl-4-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate TT)

Step1—3-[4-[3-[(2S)-2-[[(4-Methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300mg, 887 umol, Intermediate HP) and1-(4-methoxyphenyl)-N-methyl-N-[[(2S)-4-prop-2-ynylmorpholin-2-yl]methyl]methanamine (383 mg, 1.33 mmol, Intermediate RQ) in DMF (20 mL)was added Cs₂CO₃ (1.45 g, 4.44 mmol), CuI (50.7 mg, 266 umol),Pd(PPh₃)₂Cl₂ (187 mg, 266 umol) and 4Å molecular sieves (20 mg). Thereaction mixture was stirred at 80° C. for 2 hours under N₂. Oncompletion, the reaction mixture was filtered. The filtrate was washedwith water (100 mL) and extracted with ethyl acetate (2×40 mL). Thecombined organic phase was washed with brine (2×40 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo to give residue.The residue was purified by reverse phase HPLC (0.1% FA condition) togive the title compound (285 mg, 58% yield) as brown solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.13 (s, 1), 8.15 (s, 2H), 7.21-7.15 (m, 3H), 7.13-7.09(m, 1H), 6.83-6.79 (m, 2H), 5.41 (d, J=5.6, 12.8 Hz, 1H), 3.83-3.77 (m,2H), 3.69 (s, 4H), 3.64 (s, 4H), 3.56-3.51 (m, 5H), 2.39 (d, J=6.0 Hz,2H), 2.35-2.26 (m, 2H), 2.15 (s, 3H), 2.10-2.05 (m, 1H), 2.03-1.96 (m,2H).

Step 2—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a mixture of3-[4-[3-[(2S)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (285mg, 522 umol) in EA (20 mL) and IPA (10 mL) was added Pd/C (50.0 mg, 10wt %), Pd(OH)₂/C (50.0 mg, 10 wt %) and (Boc)₂O (171 mg, 783 umol). Thesuspension was degassed under vacuum and purged with H₂ three times. Themixture was then stirred at 25° C. for 16 hours under H₂ (50 psi)atmosphere. On completion, the reaction mixture was filtrated andfiltrate was concentrated in vacuo to give residue. The residue waspurified by reverse phase HPLC (0.1% FA condition) to give titlecompound (130 mg, 45% yield) as a brown solid. LC-MS (ESI⁺) m/z 530.4(M+H)⁺.

Step3—3-[3-Methyl-4-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate (130 mg, 245 umol) inDCM (2 mL) was added TFA (83.9 mg, 736 umol). The reaction mixture wasstirred at 25° C. for 2 hours. On completion, the reaction mixture wasconcentrated in vacuo to give title compound (133 mg, 100% yield, TFAsalt) as brown oil. LC-MS (ESI⁺) m/z 430.4 (M+H)⁺.

3-[3-Methyl-4-[3-[(2R)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate TU)

Step1—3-[4-[3-[(2R)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of1-(4-methoxyphenyl)-N-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]methanamine (450 mg, 1.56 mmol, Intermediate TO) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl) piperidine-2,6-dione (352mg, 1.04 mmol, Intermediate HP) in DMF (10 mL) was added Cs₂CO₃ (1.36 g,4.16 mmol), CuI (39.6 mg, 208 umol), 4Å molecular sieves (50 mg) andPd(PPh₃)₂Cl₂ (146.03 mg, 208.1 umol) at 25° C. The reaction mixture wasstirred at 80° C. for 2 hrs. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was diluted with water 30 mL, and then extracted with EA(3×50 mL). The combined organic layers were washed with brine and driedover Na₂SO₄, filtered and the filtrate was concentrated in vacuo to givea residue. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (355 mg, 63% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 8.15 (s, 1H), 7.20-7.14 (m, 4H),7.13-7.08 (m, 1H), 7.02 (t, J=8.0 Hz, 1H), 6.80 (d, J=8.8 Hz, 3H), 5.40(dd, J=5.2 Hz, 1H), 3.79 (d, J=10.0 Hz, 2H), 3.68 (s, 4H), 3.63 (s, 3H),3.60 (d, J=7.2 Hz, 2H), 2.91 (d, J=11.6 Hz, 2H), 2.74-2.64 (m, 4H), 2.37(d, J=6.0 Hz, 2H), 2.30-2.25 (m, 1H), 2.14 (s, 3H), 2.03-1.97 (in, 1H);LC-MS (ESI⁺) m/z 546.3 (M+H)⁺.

Step 2—Tert-ButylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of3-[4-[3-[(2R)-2-[[(4-methoxyphenyl)methyl-methyl-amino]methyl]morpholin-4-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (355mg, 651 umol) in EA (20 mL) and IPA (10 mL) was added Pd/C (180 mg, 20wt %), Pd(OH)₂/C (dry) (180 mg, 10 wt %) and (Boc)₂O (213 mg, 976 umol,224 uL) at 25° C. The reaction mixture was stirred at 25° C. for 2 hrsunder H₂ (50 Psi) atmosphere. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was purified by reverse phase (0.1% FA) to give the titlecompound (225 mg, 65% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.08 (s, 1H), 7.00-6.91 (m, 2H), 6.89-6.84 (m, 1H), 5.36 (dd, J=5.2Hz, 1H), 3.78 (d, J=11.2 Hz, 1H), 3.55 (s, 3H), 3.47 (s, 1H), 3.22 (d,J=4.8 Hz, 1H), 3.17 (d, J=6.8 Hz, 1H), 2.96-2.87 (m, 3H), 2.80 (d, J=8.8Hz, 3H), 2.73-2.58 (m, 4H), 2.42-2.31 (m, 3H), 2.06-1.94 (m, 2H),1.79-1.68 (m, 3H), 1.37 (s, 9H); LC-MS (ESI⁺) m/z 530.3 (M+H)⁺.

Step3—3-[3-Methyl-4-[3-[(2R)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate (120 mg, 227 umol) inDCM (2 mL) was added HCl/dioxane (4 M, 1 mL) at 25° C. The reactionmixture was stirred at 25° C. for 2 hrs. On completion, the reactionmixture was concentrated in vacuo to give the title compound (95.0 mg,98% yield) as a white solid. LC-MS (ESI⁺) m/z 430.3 (M+H)⁺.

Benzyl N-methyl-N-[2-[(2R)-4-prop-2-ynylmorpholin-2-yl]ethyl]carbamate(Intermediate TV)

Step 1—Tert-butyl (2R)-2-(2-aminoethyl)morpholine-4-carboxylate

A mixture of tert-butyl (2R)-2-(cyanomethyl)morpholine-4-carboxylate(3.86 g, 17.0 mmol, synthesized via Steps 1-2 of Intermediate RN) andRaney-Ni (3.00 g, 35.0 mmol) in MeOH (120 mL) and NH₃·H₂O (12 mL) wasstirred at 25° C. for 4 hours under H₂ (45 Psi). On completion, themixture was filtered, and the filter cake was washed with MeOH (50 mL).The filtrate and washing were combined and concentrated in vacuo to givethe title compound (3.90 g, 99% yield) as light yellow gum. ¹H NMR (400MHz, CDCl₃) δ 3.87-3.84 (m, 3H), 3.53-3.44 (m, 2H), 2.87-2.81 (m, 3H),2.65 (m, 1H), 1.65-1.56 (m, 4H), 1.47 (s, 9H).

Step 2—Tert-Butyl(2R)-2-[2-(benzyloxycarbonylamino)ethyl]morpholine-4-carboxylate

To a solution of tert-butyl (2R)-2-(2-aminoethyl)morpholine-4-carboxylate (3.90 g, 16.9 mmol) and TEA (3.55 g, 35.0 mmol)in DCM (50 mL) was added CbzCl (3.03 g, 17.7 mmol) at 0° C. The mixturewas stirred at 0-10° C. for 1 hour. On completion, the mixture waswashed with water (20 mL) and concentrated in vacuo. The residue wasdissolved in EA (50 mL), washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (6.00 g,97% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.33 (m,5H), 5.18-5.16 (m, 1H), 5.10 (s, 2H), 4.12-3.83 (m, 3H), 3.48-3.40 (m,4H), 2.90 (m, 1H), 2.62-2.61 (m, 1H), 1.44 (s, 9H).

Step 3—Tert-Butyl(2R)-2-[2-[benzyloxycarbonyl(methyl)amino]ethyl]morpholine-4-carboxylate

To a solution of tert-butyl(2R)-2-[2-(benzyloxycarbonylamino)ethyl]morpholine-4-carboxylate (6.00g, 16.4 mmol) in THF (60 mL) was added NaH (1.32 g, 33.0 mmol, 60% oildispersion) at 0° C. The mixture was stirred at 0° C. for 30 minutes.Then MeI (7.01 g, 49.3 mmol) was added to the reaction mixture at 0° C.The mixture was stirred at 0-25° C. for another 3 hours. On completion,the reaction was quenched with sat. aq. NH₄Cl (10 mL). The mixture wasdiluted with water (50 mL), then extracted with EA (3×50 mL). Thecombined organic layer was washed with brine (10 mL), dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel to give the title compound (5.20 g, 83%yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.31 (m, 5H),5.13 (s, 2H), 3.86-3.82 (m, 3H), 3.43-3.40 (m, 4H), 2.99-2.83 (m, 4H),2.69-2.52 (m, 1H), 1.74-1.62 (m, 2H), 1.47 (s, 9H).

Step 4—Benzyl N-methyl-N-[2-[(2R)-morpholin-2-yl]ethyl]carbamate

To a solution of tert-butyl(2R)-2-[2-[benzyloxycarbonyl(methyl)amino]ethyl]morpholine-4-carboxylate(5.20 g, 13.7 mmol) in DCM (30 mL) was added TFA (10 mL) at 25° C. Themixture was stirred at 25° C. for 2 hours. On completion, the mixturewas concentrated in vacuo to give the title compound (5.30 g, 98% yield,TFA salt) as light yellow gum.

Step 5—BenzylN-methyl-N-[2-[(2R)-4-prop-2-ynylmorpholin-2-yl]ethyl]carbamate

To a mixture of benzylN-methyl-N-[2-[(2R)-morpholin-2-yl]ethyl]carbamate (5.30 g, 13.5 mmol,TFA salt) and K₂CO₃ (7.59 g, 54.9 mmol) in THF (60 mL) was added3-bromoprop-1-yne (1.63 g, 13.7 mmol) at 25° C. The mixture was stirredat 25° C. for 16 hours. On completion, the mixture was filtered, and thefilter cake was washed with EA (20 mL). The filtrate and washing werecombined and concentrated in vacuo. The residue was purified by columnchromatography on silica gel to give the title compound (2.90 g, 67%yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.31 (m, 5H),5.13 (d, J=3.2 Hz, 2H), 3.87 (t, J=13.2 Hz, 1H), 3.70-3.46 (m, 2H), 3.40(t, J=7.6 Hz, 2H), 3.28 (d, J=10.8 Hz, 2H), 2.94 (s, 3H), 2.79-2.63 (m,2H), 2.44-2.33 (m, 1H), 2.27 (t, J=2.4 Hz, 1H), 2.16-2.06 (m, 1H),1.76-1.63 (m, 2H).

3-[3-Methyl-5-[3-[(2R)-2-[2-(methylamino)ethyl]morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate TW)

Step 1—BenzylN-[2-[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]ethyl]-N-methyl-carbamate

A mixture of benzylN-methyl-N-[2-[(2R)-4-prop-2-ynylmorpholin-2-yl]ethyl]carbamate (1.93 g,6.11 mmol, Intermediate TV),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.38g, 4.08 mmol, Intermediate HN), CuI (165 mg, 866 umol), Pd(PPh₃)₂Cl₂(580 mg, 826 umol), Cs₂CO₃ (6.65 g, 20.4 mmol) and 4Å molecular sieves(1.00 g) in DMF (30 mL) was stirred at 80° C. for 2 hours under N₂. Oncompletion, the reaction mixture was cooled to 25° C. The mixture wasfiltered and the filter cake was washed with EA (20 mL). The filtrateand washing were combined and concentrated in vacuo. The residue waspurified by reversed phase flash (FA condition) to give the titlecompound (1.50 g, 64% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.13 (s, 1H), 7.36-7.29 (m, 6H), 7.17-7.09 (m, 2H),5.41-5.36 (m, 1H), 5.05 (s, 2H), 3.85-3.76 (m, 1H), 3.49 (s, 3H),3.42-3.38 (m, 3H), 3.26 (m, 1H), 2.86-2.82 (m, 4H), 2.76-2.68 (m, 2H),2.65-2.62 (m, 1H), 2.52-2.52 (m, 3H), 2.31-2.25 (m, 1H), 2.06-1.98 (m,2H), 1.61-1.57 (m, 2H).

Step 2—BenzylN-[2-[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]ethyl]-N-methyl-carbamate

A mixture of benzylN-[2-[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]ethyl]-N-methyl-carbamate(1.50 g, 2.61 mmol), Pd/C (400 mg, 10 wt %), and Pd(OH)₂/C (400 mg, 10wt %) in THF (60 mL) was stirred at 25° C. for 2 hours under H₂ (15psi). On completion, the mixture was filtered, and the filter cake waswashed with EA (10mL). The filtrate and washing were combined andconcentrated in vacuo. The residue was purified by reversed phase flashchromatography (FA condition) to give the title compound (960 mg, 58%yield) as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H),7.37-7.31 (m, 5H), 6.92-6.84 (m, 2H), 6.72 (d, J=8.0 Hz, 1H), 5.26-5.18(m, 1H), 5.13 (s, 2H), 3.92-3.81 (m, 1H), 3.75-3.58 (m, 2H), 3.42 (s,3H), 3.41-3.35 (m, 2H), 2.93 (s, 3H), 2.80-2.68 (m, 7H), 2.56-2.46 (m,2H), 2.29-2.19 (m, 2H), 2.08-1.96 (m, 1H), 1.95-1.85 (m, 2H), 1.71-1.58(m, 2H).

Step3—3-[3-Methyl-5-[3-[(2R)-2-[2-(methylamino)ethyl]morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of benzylN-[2-[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]ethyl]-N-methyl-carbamate (950 mg, 1.52 mmol) inDCM (10 mL) was added a solution of hydrogen bromide (2.30 mL, 13.9mmol, 33% solution) in HOAc at 20° C. The mixture was stirred at 20° C.for 3 hours. On completion, the mixture was concentrated in vacuo at 20°C. The residue was diluted with water and lyophilized to give the titlecompound (790 mg, 98% yield, HBr salt) as light yellow solid. LC-MS(ESI⁺) m/z 444.3 (M+H)⁺.

Benzyl N-methyl-N-[2-[(2S)-4-prop-2-ynylmorpholin-2-yl]ethyl]carbamate(Intermediate TX)

Step 1—Tert-Butyl (2S)-2-(2-aminoethyl)morpholine-4-carboxylate

To a solution of tert-butyl (2S)-2-(cyanomethyl)morpholine-4-carboxylate(4.00 g, 17.6 mmol, synthesized via Steps 1-2 of Intermediate RL) inMeOH (20 mL) was added NH₃·H₂O (2.08 g, 19.5 mmol, 2.29 mL, 33%solution) and Raney-Ni (1.51 g, 17.6 mmol). The reaction mixture wasstirred at 25° C. for 12 hours under H₂ (50 psi). On completion, thereaction mixture was filtered and the filter cake was washed with MeOH.Then the filtrate was concentrated in vacuo to give the title compound(4.00 g, 98% yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ3.84-3.60 (m, 4H), 3.43-3.33 (m, 4H), 2.90-2.77 (m, 1H), 2.59 (s, 2H),1.51-1.25 (m, 11H).

Step 2—Tert-Butyl(2S)-2-[2-(benzyloxycarbonylamino)ethyl]morpholine-4-carboxylate

To a solution of tert-butyl(2S)-2-(2-aminoethyl)morpholine-4-carboxylate (3.50 g, 15.2 mmol) andTEA (3.08 g, 30.3 mmol, 4.23 mL) in DCM (40 mL) was added CbzCl (2.85 g,16.7 mmol, 2.38 mL). The mixture was stirred at 25° C. for 3 hrs. Oncompletion, the mixture was diluted with H₂O (20 mL) and extracted withDCM (2×40 mL). The organic phase was dried over Na₂SO₄, and thenconcentrated in vacuo to give the title compound (5.50 g, 99% yield) asyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.32 (m, 5H), 5.25-5.06 (m,2H), 4.01-3.69 (m, 3H), 3.57-3.34 (m, 3H), 3.34-3.22 (m, 1H), 2.98-2.82(m, 1H), 2.61 (s, 1H), 2.10-1.78 (m, 1H), 1.76-1.55 (m, 2H), 1.47 (s,9H).

Step 3—Tert-Butyl(2S)-2-[2-[benzyloxycarbonyl(methyl)amino]ethyl]morpholine-4-carboxylate

To a solution of tert-butyl(2S)-2-[2-(benzyloxycarbonylamino)ethyl]morpholine-4-carboxylate (2.00g, 5.49 mmol) in THF (40 mL) was added NaH (439 mg, 10.9 mmol, 60% oildispersion) at 0° C. The reaction mixture was stirred at 25° C. for 30minutes, and then MeI (1.95 g, 13.7 mmol, 854 uL) was added to themixture. The mixture was stirred at 25° C. for 3 hrs. On completion, thereaction mixture was quenched with H₂O (20 mL) and extracted with EA(2×40 mL). The organic phase was dried over Na₂SO₄, filtered and thefiltrate was concentrated in vacuo to give a residue. The residue waspurified by column chromatography to give the title compound (1.30 g,62% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.28 (m, 5H),5.14 (s, 2H), 4.02-3.72 (m, 3H), 3.56-3.27 (m, 4H), 3.00-2.81 (m, 4H),2.71-2.50 (m, 1H), 1.79-1.63 (m, 2H), 1.47 (s, 9H).

Step 4—Benzyl N-methyl-N-[2-[(2S)-morpholin-2-yl]ethyl]carbamate

To a solution of tert-butyl(2S)-2-[2-[benzyloxycarbonyl(methyl)amino]ethyl]morpholine-4-carboxylate(1.20 g, 3.17 mmol) in DCM (10 mL) was added TFA (4.62 g, 40.5 mmol,3.00 mL). The reaction mixture was stirred at 25° C. for 2 hrs. Oncompletion, the residue was filtered and the filtrate was concentratedin vacuo to give the title compound (1.20 g, 96% yield, TFA) as yellowoil. LC-MS (ESI⁺) m/z 279.1 (M+H)⁺.

Step 5—BenzylN-methyl-N-[2-[(2S)-4-prop-2-vnylmorpholin-2-yl]ethyl]carbamate

To a solution of benzylN-methyl-N-[2-[(2S)-morpholin-2-yl]ethyl]carbamate (1.30 g, 3.31 mmol,TFA) and 3-bromoprop-1-yne (394 mg, 3.31 mmol, 285 uL) in THF (20 mL)was added K₂CO₃ (1.37 g, 9.94 mmol). The reaction mixture was stirred at25° C. for 16 hrs. On completion, the reaction mixture was diluted withwater (30 mL) and extracted with EA (3×80 mL). The combined organiclayers was dried over Na₂SO₄, filtered and concentrated in vacuo to givea residue. The residue was purified by column chromatography to give thetitle compound (900 mg, 85% yield) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 7.42-7.28 (m, 5H), 5.13 (s, 2H), 3.87 (t, J=12.4 Hz, 1H),3.70-3.47 (m, 2H), 3.40 (t, J=7.2 Hz, 2H), 3.28 (d, J=9.6 Hz, 2H), 2.94(s, 3H), 2.79-2.62 (m, 2H), 2.39 (t, J=10.8 Hz, 1H), 2.30-2.23 (s, 1),2.16-2.06 (m, 1), 1.75-1.63 (m, 2H).

3-[3-Methyl-5-[3-[(2S)-2-[2-(methylamino)ethyl]morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate TY)

Step 1—BenzylN-[2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]ethyl]-N-methyl-carbamate

To a solution of benzylN-methyl-N-[2-[(2S)-4-prop-2-ynylmorpholin-2-yl]ethyl]carbamate (350 mg,1.11 mmol, Intermediate TX) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (249mg, 737 umol, Intermediate HN) in DMSO (10 mL) was added DIPEA (476 mg,3.69 mmol, 642 uL), CuI (14.0 mg, 73.7 umol) and Pd(PPh₃)₂Cl₂ (51.7 mg,73.7 umol). The reaction mixture was stirred at 80° C. for 2 hrs underN₂. On completion, the mixture was filtered, and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (120 mg,28% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H),7.38-7.28 (m, 6H), 7.24-7.09 (m, 2H), 5.40 (dd, J=5.2, 12.8 Hz, 1H),5.06 (s, 2H), 3.72-3.39 (m, 6H), 3.35 (s, 6H), 2.92-2.80 (m, 5H),2.77-2.71 (m, 1H), 2.66-2.59 (m, 2H), 2.07-2.00 (m, 1H), 1.74-1.55 (m,2H); LC-MS (ESI⁺) m/z 574.3 (M+H)⁺.

Step 2—BenzylN-[2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]ethyl]-N-methyl-carbamate

To a solution of benzylN-[2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]ethyl]-N-methyl-carbamate (100 mg, 174 umol)in THF (20 mL) was added Pd(OH)₂/C (2 mg, 10 wt %) and Pd/C (2 mg, 10 wt%). The reaction mixture was stirred at 25° C. for 12 hrs under H₂ (15psi). On completion, the residue was filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.10% FA condition) to give the title compound (80.0 mg,79% yield) as a yellow solid. LC-MS (ESI⁺) m/z 578.3 (M+H)⁺.

Step3—3-[3-Methyl-5-[3-[(2S)-2-[2-(methylamino)ethyl]morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of benzylN-[2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]morpholin-2-yl]ethyl]-N-methyl-carbamate (80.0 mg, 138 umol) inDCM (2 mL) was added HBr/CH₃COOH (8.66 umol, 1 mL, 35% solution). Thereaction mixture was stirred at 20° C. for 4 hrs. On completion, themixture was concentrated in vacuo to give the title compound (70.0 mg,96% yield, HBr) as a white solid. LC-MS (ESI⁺) m/z 444.3 (M+H)⁺.

1-[4-(1-Amino-2,2,2-trifluoro-ethyl)phenyl]-4-nitro-pyrazole-3-carboxamid(Intermediate TZ)

Step 1—Methyl 1-(4-formylphenyl)-4-nitro-pyrazole-3-carboxylate

To a solution of methyl1-[4-(hydroxymethyl)phenyl]-4-nitro-pyrazole-3-carboxylate (5.00 g, 18.0mmol, synthesized via Step 1 of Intermediate GB) in DCM (100 mL) wasadded DMP (9.18 g, 21.6 mmol). The reaction mixture was stirred at 20°C. for 12 hrs. On completion, the mixture was quenched with sat. Na₂S₂O₃(100 mL) and sat. NaHCO₃ (100 mL), stirred and extracted with DCM (2×100mL). The organic layer was washed with brine (200 mL), dried withNa₂SO₄, filtered and the filtrate was concentrated in vacuo. The residuewas triturated with PE/DCM=2:1 (50 mL), filtered and the filter cake wasdried in vacuo to give the title compound (4.30 g, 87% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 9.90 (s, 1H),8.25-8.19 (m, 2H), 8.17-8.09 (m, 2H), 3.96 (s, 3H).

Step 2—Methyl4-nitro-1-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)phenyl]pyrazole-3-carboxylate

To a solution of methyl1-(4-formylphenyl)-4-nitro-pyrazole-3-carboxylate (4.30 g, 15.6 mmol) inTHF (80 mL) was added TMSCF₃ (4.44 g, 31.3 mmol) and Cs₂CO₃ (10.2 g,31.3 mmol). The reaction mixture was stirred at 20° C. for 2 hrs. ThenHCl/dioxane (30 mL) was added and the mixture was stirred at 20° C. for10 hrs. On completion, the mixture was quenched with water, extractedwith EA (2×70 mL). The organic layer was washed with water, thenconcentrated in vacuo. The residue was purified by silica gelchromatography (SiO₂) to give the title compound (1.20 g, 22% yield) asyellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 8.03-7.97 (m, 2H),7.70 (d, J=8.8 Hz, 2H), 7.02 (d, J=5.6 Hz, 1H), 5.37-5.27 (m, 1H), 3.95(s, 3H).

Step3—4-Nitro-1-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)phenyl]pyrazole-3-carboxamide

To a solution of methyl4-nitro-1-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)phenyl]pyrazole-3-carboxylate(1.20 g, 3.48 mmol) in THF (20 mL) was add NH₃H₂O (9.75 g, 69.5 mmol,25% solution). The reaction mixture was stirred at 75° C. for 10 hrs. Oncompletion, the mixture was diluted with water (40 mL), then extractedwith EA (2×40 mL). The organic layer was concentrated in vacuo. Theresidue was purified by silica gel chromatography (SiO₂) to give thetitle compound (720 mg, 63% yield) as an off-white solid. ¹H NMR (400MHz, DMSO-d₆) 9.65 (s, 1H), 8.19 (s, 1H), 8.06-7.96 (m, 2H), 7.91 (s,1H), 7.73-7.65 (m, 2H), 7.00 (d, J=5.6 Hz, 1H), 5.34-5.26 (m, 1H).

Step4—[1-[4-(3-Carbamoyl-4-nitro-pyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethyl]methanesulfonate

To a solution of4-nitro-1-[4-(2,2,2-trifluoro-1-hydroxy-ethyl)phenyl]pyrazole-3-carboxamide(720 mg, 2.18 mmol) and TEA (662 mg, 6.54 mmol) in a mixed solvent ofDCM (10 mL) and THF (10 mL) was added MsCl (500 mg, 4.36 mmol) at 0° C.Then the reaction mixture was stirred at 20° C. for 3 hrs. Oncompletion, the mixture was quenched with water (50 mL), then extractedwith DCM (2×50 mL). The organic layer was washed with brine (50 mL),dried with Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (SiO₂) to give the title compound(850 mg, 95% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.69(s, 1H), 8.22 (s, 1H), 8.13-8.08 (m, 2H), 7.94 (s, 1H), 7.83-7.74 (m,2H), 6.70-6.60 (m, 1H), 3.33 (s, 3H).

Step5—1-[4-(1-Azido-2,2,2-trifluoro-ethyl)phenyl]-4-nitro-pyrazole-3-carboxamide

To a solution of[1-[4-(3-carbamoyl-4-nitro-pyrazol-1-yl)phenyl]-2,2,2-trifluoro-ethyl]methanesulfonate(500 mg, 1.22 mmol) and TBAI (45.2 mg, 122 umol) in DMF (10 mL) wasadded NaN₃ (159 mg, 2.45 mmol). The reaction mixture was stirred at 25°C. for 1 hr and then heated at 80° C. for 12 hrs. On completion, themixture was diluted with water (30 mL), then extracted with DCM (2×30mL). The organic layer was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(130 mg, 30% yield) as a white solid. LC-MS (ESI⁺) m/z 356.1(M+H)⁺.

Step6—1-[4-(1-Amino-2,2,2-trifluoro-ethyl)phenyl]-4-nitro-pyrazole-3-carboxamide

To a solution of1-[4-(1-azido-2,2,2-trifluoro-ethyl)phenyl]-4-nitro-pyrazole-3-carboxamide(130 mg, 366 umol) in a mixed solvent of H₂O (0.2 mL) and THF (10 mL)was added PPh₃ (192 mg, 732 umol). The mixture was stirred at 20° C. for2 hrs, then the mixture was heated at 80° C. for 10 hrs. On completion,the mixture was concentrated in vacuo. The residue was purified bysilica gel chromatography (SiO₂) to give the title compound (90.0 mg,72% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H),8.19 (s, 1H), 8.01-7.94 (m, 2H), 7.91 (s, 1H), 7.74-7.68 (m, 2H), 4.62(s, 1H), 2.65-2.54 (m, 2H); LC-MS (ESI⁺) m/z 330.1 (M+H)⁺.

3-[5-[3-[2-(2-Hydroxyethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate UA)

Step1—3-[5-[3-[2-(2-Hydroxyethoxy)ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HN) and 2-(2-prop-2-ynoxyethoxy)ethanol (639mg, 4.44 mmol, Intermediate LC) in DMSO (15 mL) was added CuI (56.3 mg,295 umol), Pd(PPh₃)₂Cl₂ (103 mg, 147 umol), DIPEA (955 mg, 7.39 mmol), 4Å moleculare sieves (0.5 g) and P (t-Bu)₃ (2.30 g, 1.48 mmol, 13 wt %).The reaction mixture was heated at 80° C. for 2 hours. On completion,the reaction mixture was quenched by water (30 mL), and then extractedwith EA (3×40 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (FA condition) to give the title compound (590 mg,99% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s,1H), 7.33 (d, J=0.8 Hz, 1H), 7.20-7.09 (m, 2H), 5.40 (dd, J=5.2, 12.4Hz, 1H), 4.43-4.37 (m, 2H), 3.67-3.62 (m, 2H), 3.61-3.56 (m, 2H),3.52-3.49 (m, 2H), 3.46-3.42 (m, 3H), 3.34 (s, 3H), 2.96-2.81 (m, 1H),2.76-2.59 (m, 2H), 2.07-1.94 (m, 1H); LC-MS (ESI⁺) m/z 402.1 (M+H)⁺.

Step2—3-[5-[3-[2-(2-Hydroxyethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-[5-[3-[2-(2-hydroxyethoxy)ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(650 mg, 1.62 mmol) in THF (20 mL) was added Pd/C (100 mg, 10 wt %) andPd(OH)₂/C (100 mg, 10 wt %) under N₂. The suspension was degassed undervacuum and purged with H₂ three times. The mixture was stirred under H₂(15 psi) at 25° C. for 16 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give the title compound (570 mg,86% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 7.04 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.92-6.82 (m, 1H), 5.33 (dd,J=5.2, 12.8 Hz, 1), 4.58 (t, J=5.2 Hz, 1), 3.54-3.37 (m, 10H), 2.97-2.82(m, 1H), 2.76-2.57 (m, 4H), 2.01 (s, 1H), 1.87-1.72 (m, 2H); LC-MS(ESI⁺) m/z 406.2 (M+H)⁺.

2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethylmethanesulfonate (Intermediate UB)

To a solution of3-[5-[3-[2-(2-hydroxyethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (100 mg, 246 umol) and TEA (74.8 mg, 739 umol) inDCM (4 mL) was added MsCl (42.3 mg, 369 umol) at 0° C., the mixture wasstirred at 25° C. for 1 hour. On completion, the reaction mixture wasquenched by water (15 mL), and then extracted with DCM (3×15 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (110 mg, 92% yield) aslight yellow oil. LC-MS (ESI⁺) m/z 484.1 (M+H)⁺.

2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]acetaldehyde(Intermediate UC)

To a solution of3-[5-[3-[2-(2-hydroxyethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (270 mg, 666 umol, Intermediate UA) in THF (10 mL)was added DMP (339 mg, 799 umol). The mixture was stirred at 25° C. for4 hrs. On completion, the reaction mixture was quenched by saturatedNa₂S₂O₃ (6 mL) and saturated NaHCO₃ (6 mL) at 25° C., stirred for 30minutes. Then the mixture was extracted with DCM (3×30 mL). The combinedorganic layers dried over Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (0.1% FA condition) to give the title compound (150 mg, 56%yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s,1H), 9.62 (s, 1H), 7.10-6.92 (m, 2H), 6.85-6.72 (s, 1H), 5.41-5.38 (m,1H), 4.18 (s, 1), 3.72-3.65 (m, 1), 3.60-3.35 (m, 6H), 3.34-3.25 (m,3H), 2.99-2.81 (m, 1H), 2.75-2.55 (m, 4H), 2.05-1.91 (m, 1H), 1.88-1.70(m, 2H); LC-MS (ESI⁺) m/z 404.2 (M+H)⁺.

4-Amino-1-[4-[1-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethylamino]-2,2,2-trifluoro-ethyl]phenyl]pyrazole-3-carboxamide(Intermediate UD)

Step1—1-[4-[1-[2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethylamino]-2,2,2-trifluoro-ethyl]phenyl]-4-nitro-pyrazole-3-carboxamide

To a solution of2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]acetaldehyde (98.0 mg, 243 umol, Intermediate UC) and1-[4-(1-amino-2,2,2-trifluoro-ethyl)phenyl]-4-nitro-pyrazole-3-carboxamide(80.0 mg, 243 umol, Intermediate TZ) in THF (3 mL) was added HOAc (14.6mg, 243 umol). The mixture pH was adjusted to 5-6 and NaBH(OAc)₃ (103mg, 486 umol) was added into the mixture. The reaction mixture wasstirred at 25° C. for 12 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (25.0 mg, 14% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.63 (s, 1), 8.18 (s,1), 7.99 (d, J=8.8 Hz, 2H), 7.92 (s, 1H), 7.68 (d, J=8.8 Hz, 2H),7.02-6.96 (m, 2H), 6.84 (d, J=8.0 Hz, 1), 6.54 (s, 1), 5.32 (dd, J=5.2,12.8 Hz, 1), 4.70-4.55 (m, 1H), 3.50-3.44 (m, 6H), 3.37 (t, J=6.4 Hz,2H), 3.30 (s, 3H), 2.93-2.82 (m, 2H), 2.72-2.66 (m, 1H), 2.66-2.62 (m,4H), 2.03-1.95 (m, 1H), 1.84-1.74 (m, 2H); LC-MS (ESI⁺) m/z 717.0(M+H)⁺.

Step9—4-Amino-1-[4-[1-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethylamino]-2,2,2-trifluoro-ethyl]phenyl]pyrazole-3-carboxamide

To a solution of1-[4-[1-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethylamino]-2,2,2-trifluoro-ethyl]phenyl]-4-nitro-pyrazole-3-carboxamide(22.0 mg, 29.2 umol) in THF (4 mL) was added PtO₂ (6.62 mg, 29.2 umol).The reaction mixture was stirred at 25° C. for 4 hrs under H₂ (15 psi)atmosphere. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (20.0 mg, 100% yield)as a yellow solid. LC-MS (ESI⁺) m/z 687.3 (M+H)+

4-[2-[2-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate UE)

Step1—Tert-butylN-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

A solution of 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione(550 mg, 1.99 mmol, Intermediate R), tert-butylN-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(500 mg, 1.31 mmol, CAS #189209-27-6) and DIPEA (1.36 g, 10.5 mmol) inDMSO (20 mL) was stirred at 120-130° C. for 16 hours. On completion, thereaction mixture was cooled to rt and diluted with water (150 mL), thenextracted with EA (3×80 mL). The combined organic layer was washed withbrine (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography on silica gel to givecrude product (800 mg). The crude product was purified by reversed phasechromatography (phase A: 0.1% FA water, B: CH₃CN, 53% CH₃CN) to thetitle compound (490 mg, 58% yield) as yellow gum. ¹H NMR (400 MHz,CDCl₃) δ 8.29 (s, 1H), 7.50 (dd, J=7.2 Hz, J=8.4 Hz, 1H), 7.12 (d, J=7.2Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.51 (m, 1H), 5.09 (m, 1H), 4.94-4.90(m, 1H), 3.74-3.63 (m, 18H), 3.55-3.54 (m, 4H), 3.32-3.31 (m, 2H),2.83-2.77 (m, 3H), 2.15 (m, 1H), 1.45 (s, 9H). LC-MS (ESI⁺) m/z 659.3(M+Na), 537.3 (M-Boc+1)⁺.

Step2—4-[2-[2-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (490 mg, 770umol) in DCM (10 mL) was added 4.0 M HCl/dioxane (5 mL) at rt, and themixture was stirred at rt for 2 hours. On completion, the mixture wasconcentrated in vacuo to give the title compound (530 mg, quant. crudeyield, HCl) as yellow gum. LC-MS (ESI⁺) m/z 537.3 (M+H)⁺.

3,6,9,12,15-pentaoxaheptadecanedioic Acid (Intermediate UF)

Step 1—Di-Tert-Butyl 3,6,9,12,15-pentaoxaheptadecanedioate

To a solution of NaH (60% dispersion in mineral oil, 4.54 g, 113.4 mmol)in THF (200 mL) was added2,2′-((oxybis(ethane-2,1-diyl))bis(oxy))diethanol (10 g, 51.5 mmol, CAS#112-60-7) portion wise at 0° C. After addition, the mixture was stirredat 0° C. for 1 h, then tert-butyl 2-bromoacetate (22 g, 113.4 mmol) wasadded. After addition, the mixture was warmed to rt and stirredovernight. The mixture was quenched by addition of water, then extractwith EtOAc (3×50 mL). The combined organic layers was washed with brine(100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography eluting withPE/EA=4/1 to give the title compound (5.5 g, 25.2%) as an colorless oil.LC/MS (ESI, m/z): [M+1]⁺=423.1.

Step 2—3,6,9,12,15-pentaoxaheptadecanedioic Acid

To a solution of di-tert-butyl 3,6,9,12,15-pentaoxaheptadecanedioate(5.5 g, 13 mmol) in DCM (2 mL) was added 4M HCl in dioxane (18 mL). Themixture was stirred at rt overnight. The mixture was concentrated invacuo to give the the title compound (3.5 g, 87% yield). LC/MS (ESI,m/z): [M+1]⁺=311.0.

3-(6-Amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (IntermediateUG)

Step 1—6-nitro-9H-pyrido[2,3-b]indole

To a mixture 68%-70% nitric acid in H₂O (20 mL) and fuming nitric acid(20 mL) was added 9H-pyrido[2,3-b]indole (2.5 g, 14.88 mmol) in portionsat room temperature and the temperature was maintained under 30° C. Themixture was stirred at 25° C. for 1 h. Then the mixture was set asideovernight at 0° C. A lot of solid was formed. The resulting solid wasfiltered off and stirred with dilute ammonium hydroxide solution (50 mL)(33% in H₂O). It was then filtered off and washed with water to leavethe crude compound. The crude compound was triturated with EA andfiltrated to give 6-nitro-9H-pyrido[2,3-b]indole as a grey solid. (2.6g, yield:82%). LC/MS (ESI, m/z): [M+1]⁺=214.2

Step C:1-(4-methoxybenzyl)-3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of 6-nitro-9H-pyrido[2,3-b]indole (2.6 g, 12.2 mmol) inTHF (50 mL) was added t-BuOK (2.05 g, 18.3 mmol) at 0° C. The mixturewas stirred at 0-10° C. for 1 hour under N₂. Then a solution of[1-[(4-methoxyphenyl) methyl]-2, 6-dioxo-3-piperidyl]trifluoromethanesulfonate (6.98 g, 18.3 mmol) in THF (50 mL) was addedto the reaction mixture at 0-10° C. during 30 minutes. The mixture wasstirred at 0-10° C. for 30 minutes under N₂. The reaction was quenchedwater (40 mL) and extracted with EA (3×50 mL). The combined organiclayers were concentrated under reduced pressure. The residue wastriturated with EA and filtrated to give1-(4-methoxybenzyl)-3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dioneas a grey solid (4.95 g, yield 91%). LC/MS (ESI, m/z): [M+1]⁺=445.1

Step D: 3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of1-(4-methoxybenzyl)-3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(400 mg, 0.90 mmol) in ACN (10 mL) was added CAN (2.46 g, 0.45 mmol) inwater (3 mL) at 0° C. After the addition, the mixture was warmed up toroom temperature and stirred overnight. The reaction mixture was pouredinto water (50 mL), extract with EtOAc (3×50 mL), the combined organiclayers were concentrated under reduced pressure. The residue wastriturated with DMF/EA and filtrated to give3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione as a greysolid (130 mg, yield:44.4%). LC/MS (ESI, m/z): [M+1]⁺=325.1

Step E: 3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-(6-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (130 mg,0.401 mmol) in THF (5 mL) and EA (5 mL) was added Palladium on activatedcarbon 10% Pd (50 mg). The mixture was stirred at room temperature underH2 balloon overnight. The reaction mixture was filtered, the filtratewas concentrated under reduce pressure, the residue was triturated withDMF/EA and filtrated to give3-(6-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione as a greysolid (55 mg, yield:46.4%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),8.26-8.39 (m, 2H), 7.24-7.36 (m, 2H), 7.14 (dd, J=7.63, 4.88 Hz, 1H),6.85 (dd, J=8.63, 2.13 Hz, 1H), 5.90 (br. s., 1H), 4.87 (s, 2H),2.93-3.08 (m, 2H), 2.68 (d, J=12.26 Hz, 1H), 2.01-2.11 (m, 1H). LC/MS(ESI, m/z): [M+1]⁺=295.1.

3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (IntermediateUH)

Step 1—6-bromo-9H-pyrido[2,3-b]indole

To a stirred solution of 9H-pyrido[2,3-b]indole (3 g, 17.9 mmol, CAS#26148-68-5) in DCM (50 mL) was added Br₂ (3.4 g, 21.4 mmol) dropwise at0° C. The reaction mixture was stirred at 0° C. for 4 h. To the mixturewas added aq. NaHCO₃ (100 mL), then the solution was extracted with EA(200mL). The organic layer was washed with brine (50 mL), dried overNa₂SO₄, filtered, concentrated to give the title compound (2.7 g, 61%yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.60(dd, J=1.2 Hz, J=7.6 Hz, 1H), 8.48-8.44 (m, 2H), 7.60-7.58 (m, 1H), 7.48(d, J=8.4 Hz, 1H), 7.26 (dd, J=4.8 Hz, J=7.6 Hz, 1H). LC/MS (ESI, m/z):[M+1]⁺=247.8

Step2—3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a stirred solution of 6-bromo-9H-pyrido[2,3-b]indole (200 mg, 0.810mmol) and 18-crown-6 (43 mg, 0.162 mmol) in THF (10 mL) was added NaHMDS(0.6 mL, 2 M in THF) dropwise at −30° C. under N₂. The mixture wasstirred for 1 h at −30° C. under N₂. Then to the mixture was added asolution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yltrifluoromethanesulfonate (463 mg, 1.21 mmol) in THF (5 mL) dropwise at−30° C. under N₂. The mixture was stirred for 2 h at −30° C. The mixturewas added to aq. NH₄Cl (20 mL), then extracted with EA (50 mL). Theorganic layer was washed with brine (30 mL), dried over Na₂SO₄,filtered, concentrated and purified by column (PE/EA/DCM=10/i/1 to3/1/1) to give the title compound (220 mg, 57% yield) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 8.41 (dd, J=1.6 Hz, J=5.2 Hz, 1H), 8.29 (dd,J=1.2 Hz, J=7.6 Hz, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.45 (dd, J=2.0 Hz,J=8.8 Hz, 1H), 7.40 (d, J=8.8 Hz, 2H), 7.24-7.21 (m, 1H), 6.84 (d, J=8.8Hz, 3H), 5.90-5.87 (m, 1H), 5.01 (dd, J=13.6 Hz, J=20.4 Hz, 2H), 3.79(s, 3H), 3.09-2.88 (m, 3H), 3.27-2.24 (m, 1H). LC/MS (ESI, m/z):[M+1]⁺=479.1.

Step 3—3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

A mixture of3-(6-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(1.3 g, 2.72 mmol), MsOH (10 mL) and toluene (20 mL) was heated to 110°C. and stirred for 3 h under N₂. The solvent was concentrated to removetoluene. Then to the mixture was added EtOAc (50 mL), and the solutionwas washed with brine (50 mL) to remove MsOH. The organic layer wasdried over Na₂SO₄. The solid was filter and the filtrate wasconcentrated. The resulting residue was purified by columnchromatography on silica gel (PE/EA=1/1) to give the title compound (500mg, 51% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s,1H), 8.64 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.47(dd, J=1.6 Hz, J=4.8 Hz, 1H), 7.68-7.64 (m, 2H), 7.32 (dd, J=4.8 Hz,J=7.6 Hz, 1H), 6.06 (br s, 1H), 3.16-2.96 (m, 2H), 2.73-2.67 (m, 1H),2.16-2.13 (m, 1H). LC/MS (ESI, m/z): [M+1]⁺=358.0.

Tert-Butyl Methyl(3-(prop-2-yn-1-yloxy)propyl)carbamate (IntermediateUI)

To a solution of tert-butyl (3-hydroxypropyl)(methyl)carbamate (2 g,10.6 mmol, CAS #98642-44-5) in DCM (30 mL) was added aq. NaOH (40%, 20mL), 3-bromoprop-1-yne (1.9 g, 15.9 mmol) and TBAHS (180 mg, 0.530 mmol)at rt. The mixture was stirred at rt for 3 h. To the mixture was addedH₂O (100 mL), then the mixture was extracted with DCM (3×30 mL). Theorganic layers were washed with brine (50 mL), dried over Na₂SO₄,filtered, concentrated and purified by column (PE/EA=20/1 to 10/1 to4/1) to give the title compound (1.4 g, 58% yield) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 4.14 (d, J=2.4 Hz, 2H), 3.53 (t, J=6.4 Hz, 2H),3.29 (t, J=6.8 Hz, 2H), 2.86 (s, 3H), 2.42 (t, J=2.4 Hz, 1H), 1.83-1.80(m, 2H), 1.46 (s, 9H). LC/MS (ESI, m/z): [M+1]⁺=227.9.

2-[2-[2-[2-(4-Nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethanamine(Intermediate UJ)

Step 1—Tert-ButylN-[2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (3 g, 8.08 mmol, Intermediate AO) and4-nitro-1H-pyrazole (608 mg, 5.38 mmol) in DMF (40 mL) was added Cs₂CO₃(3.51 g, 10.7 mmol). The reaction mixture was stirred at 130° C. for 2hours. On completion, the mixture was filtered, and the filtrate wasconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (1.20 g, 57% yield) as yellowoil. LC-MS (ESI⁺) m/z 411.2 (M+Na)⁺.

Step 2—2-[2-[2-[2-(4-Nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethanamine

To a solution of tert-butylN-[2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate(750 mg, 1.93 mmol) in DCM (6 mL) was added HCl/dioxane (4 M, 4.50 mL).The reaction mixture was stirred at 20° C. for 1.5 hours. On completion,the reaction mixture was concentrated in vacuo to give the titlecompound (620 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI⁺)m/z 289.2 (M+H)⁺.

4-[2-[2-[2-[2-(4-Aminopyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate UK)

Step1—2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethanamine (670 mg,2.06 mmol, HCl salt, Intermediate UJ) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (570 mg, 2.06mmol, Intermediate R) in dioxane (20 mL) was added DIPEA (1.33 g, 10.3mmol). The reaction mixture was stirred at 120° C. for 12 hours. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by reversed phase (0.1%, FA condition) to give the titlecompound (400 mg, 36% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ11.11 (s, 1H), 8.82 (s, 1H), 8.26 (s, 1H), 7.62-7.52 (m, 1), 7.14 (d,J=8.8 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.59 (t, J=6.0 Hz, 1H), 5.06 (dd,J=5.2, 12.8 Hz, 1H), 4.33 (t, J=5.2 Hz, 2H), 3.79 (t, J=5.2 Hz, 2H),3.62-3.59 (m, 2H), 3.56-3.46 (m, 10H), 3.56-3.44 (m, 1), 2.94-2.83 (m,1H), 2.63-2.56 (m, 1H), 2.57-2.54 (m, 1H), 2.07-1.99 (m, 1H). LC-MS(ESI⁺) m/z 545.2 (M+H)⁺.

Step2—4-[2-[2-[2-[2-(4-Aminopyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione (400 mg, 735 umol) in THF (40 mL) wasadded PtO₂H₂O (50 mg, 220 umol) under N₂. The suspension was degassedunder vacuum and purged with H₂ several times. The mixture was stirredunder H₂ (15 psi) at 20° C. for 12 hours. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (370 mg, 98% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ11.10 (s, 1), 7.63-7.53 (m, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.07-7.01 (m,2H), 6.89 (s, 1), 6.60 (t, J=5.8 Hz, 1), 5.06 (dd, J=5.2, 12.8 Hz, 1),4.03 (t, J=5.6 Hz, 2H), 3.66 (t, J=5.6 Hz, 2H), 3.57-3.54 (m, 2H),3.54-3.45 (m, 10H), 2.96-2.82 (m, 1H), 2.63-2.60 (m, 1H), 2.59-2.57 (m,1H), 2.05-1.98 (m, 1H).

2-[2-[2-[2-(2-Tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]acetic Acid(Intermediate UM)

Step 1-Ethyl2-[2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl 2-[2-[2-(2-hydroxyethoxy) ethoxy] ethoxy] acetate(150 mg, 635 umol, synthesized via Step 1 of Intermediate BI) anddiacetoxyrhodium (6.00 mg, 13.6 umol) in anhydrous DCM (4 mL) was addeda solution of tert-butyl 2-diazoacetate (271 mg, 1.91 mmol, CAS#35059-50-8) in DCM (4 mL) dropwise at 0-10° C. The mixture was stirredat 25° C. for 16 hours under N₂. On completion, the reaction wasquenched with HOAc (0.1 mL). The mixture was stirred at 25° C. for 15minutes. The mixture was then concentrated in vacuo. The residue waspurified over column chromatography on silica gel (PE:EA-=5:1-3:1) togive the title compound (130 mg, 58% yield) as light green oil. ¹H NMR(400 MHz, CDCl3) δ 4.22 (q, J=7.2 Hz, 2H), 4.16 (s, 2H), 4.03 (s, 2H),3.74-3.68 (m, 12H), 1.48 (s, 9H), 1.29 (t, J=7.2 Hz, 3H).

Step2—2-[2-[2-[2-(2-Tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]aceticAcid

To a solution of ethyl 2-[2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy] ethoxy] acetate (130 mg, 371 umol) in THF (3 mL) was added asolution of lithium hydroxide hydrate (17.0 mg, 405 umol) in H₂O (1 mL)at 25° C. The mixture was stirred at 25° C. for 16 hours. On completion,the mixture was diluted with water (20 mL), acidified to pH=5 with 1.0 Maq. HCl, then extracted with EA (3×10 mL). The combined organic layerwas washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (110 mg, 92% yield) aslight green oil. ¹H NMR (400 MHz, CDCl₃) δ 4.17 (s, 2H), 4.03 (s, 2H),3.77-3.70 (m, 12H), 1.48 (s, 9H).

2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-Hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]aceticacid (Intermediate UN)

Step 1—Tert-butyl2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]acetate

A mixture of(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(180 mg, HCl, Intermediate CI),2-[2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]acetic acid(100 mg, 310 umol, Intermediate UM), HATU (155 mg, 408 umol) and DIPEA(121 mg, 936 umol) in DMF (5 mL) was stirred at 25° C. for 2 hours. Oncompletion, the reaction mixture was diluted with water (50 mL), thenextracted with EA (3×30 mL). The combined organic layer was washed withbrine (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.The residue was purified over column chromatography on silica gel(DCM:MeOH=50:1-20:1) to give the title compound (130 mg, 48% yield, 84%purity) as light yellow gum. LC-MS (ESI⁺) m/z 735.3 (M+H)⁺, 757.3(M+Na)⁺.

Step2—2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-Hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a solution of tert-butyl2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]acetate (110 mg, 125 umol) in DCM (4 mL) was added TFA (2mL) at 25° C. The mixture was stirred at 25° C. for 3 hours. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (140 mg, quant. crude yield, TFA) as light yellow gum. LC-MS(ESI⁺) m/z 679.4 (M+H)⁺.

2-[2-[2-(2-Tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]acetic Acid(Intermediate UQ)

Step 1—Ethyl 2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]acetate

To a stirring mixture of ethyl 2-[2-(2-hydroxyethoxy)ethoxy]acetate(0.80 g, 4.16 mmol, synthesized via Step 1 of Intermediate BM) anddiacetoxyrhodium (33.6 mg, 76.0 umol) in DCM (10 mL) was added asolution of tert-butyl 2-diazoacetate (1.78 g, 12.49 mmol, CAS#35059-50-8) in DCM (10 mL) drop-wise under ice-cooling bath (0° C.).After the addition, the resulting mixture was stirred at 20° C. for 16hours. Diacetoxyrhodium (33.6 mg, 76.02 umol) and tert-butyl2-diazoacetate (1.78 g, 12.49 mmol) were supplied subsequently, and theresulting mixture was stirred at 20° C. for another 4 hours. Oncompletion, the mixture was quenched with AcOH (1.2 mL) andconcentration in vacuo. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1 to 3/1) to givethe title compound (1.11 g, 87% yield) as blue oil. ¹H NMR (400 MHz,CDCl₃) δ 4.28 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 4.15 (s, 2H), 3.73-3.70(m, 8H), 1.48 (m, 9H), 1.28 (t, J=7.2 Hz, 3H).

Step 2—2-[2-[2-(2-Tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]acetic acid

To a solution of ethyl2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]acetate (1 g, 3.26mmol) in THF (40 mL) was added a solution of LiOH·H₂O (170 mg, 4.05mmol) in H₂O (20 mL). The mixture was stirred at 20° C. for 16 hours. Oncompletion, the mixture was diluted with H₂O (30 mL), adjusted to pH=4-5with 1M aq. HCl, extracted with EA (2×50 mL). The organic phases werecombined and dried over Na₂SO₄, filtered and concentrated in vacuo togive the title compound (800 mg, 88% yield) as yellowish oil.

2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-Hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]aceticAcid (Intermediate UR)

Step 1—Tert-butyl2-[2-[2-[2-[[(15)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]acetate

To a mixture of 2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy]aceticacid (200 mg, 718 umol, Intermediate UQ) and HATU (327 mg, 862 umol) inDMF (20 mL) was added DIPEA (278 mg, 2.16 umol, 375 uL) and(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (335 mg, 718 umol, HCl, IntermediateCI) subsequently, then the resulting mixture was stirred at 20° C. for16 hours. On completion, the mixture was diluted with H₂O (20 mL), thenextracted with EA (2×50 mL), the organic phase was concentrated invacuo. The residue was purified by column chromatography (SiO₂,PE/EA=1/1, EA/MeOH=40/1 to 10/1) to give the title compound (400 mg, 70%yield) as yellowish solid. LC-MS (ESI⁺) m/z 691.3 (M+H)⁺.

Step 2—(S)-Methyl13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecan-1-oate

To a solution of tert-butyl2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]acetate(100 mg, 144 umol) in MeOH (5 mL) was added HCl/dioxane (4 M, 2 mL). Themixture was stirred at 20° C. for 16 hours. On completion, the reactionmixture was concentrated in vacuo to give the title compound (150 mg,quant. crude yield) as colorless oil. LC-MS (ESI⁺) m/z 649.3 (M+H)⁺.

Step3—2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-Hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]aceticacid

To a solution of (S)-methyl13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecan-1-oate(150 mg) in THF (10 mL) was added a solution of LiOH·H₂O (200 mg, 4.77mmol) in H₂O (5 mL). The mixture was stirred at 20° C. for 20 mins. Oncompletion, the mixture was concentrated in vacuo to remove THF, thendiluted with H₂O (20 mL) and the pH was adjusted to 5 with 1.0 M aq.HCl, extracted with EA (2×40 mL). The organic phases were concentratedin vacuo to give the title compound (80 mg, 96%) as yellowish oil. LC-MS(ESI⁺) m/z 635.4 (M+H)⁺.

Tert-Butyl N-[2-[2-[2-(4-aminopyrazol-1-yl)ethoxy]ethoxy]ethyl]carbamate(Intermediate US)

Step1-Tert-butylN-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethyl]carbamate

To a solution of 2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethylmethanesulfonate (2.08 g, 6.37 mmol, synthesized via Step 1 ofIntermediate AM) and 4-nitro-1H-pyrazole (0.600 g, 5.31 mmol, CAS#2075-46-9) in DMF (40 mL) was added Cs₂CO₃ (3.46 g, 10.6 mmol). Themixture was stirred at 130° C. for 2 hours. On completion, after coolingto 25° C., the mixture was filtered, and the filtrate was concentratedin vacuo. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (1.50 g, 82% yield) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 8.29 (s, 1H), 8.00 (s, 1H), 4.90 (s, 1H), 4.28 (t,J=4.8 Hz, 2H), 3.84-3.77 (m, 2H), 3.56-3.50 (m, 4H), 3.46 (t, J=5.2 Hz,2H), 3.30-3.21 (m, 2H), 1.37 (s, 9H). LC-MS (ESI⁺) m/z 367.2 (M+Na)⁺.

Step 2—Tert-butylN-[2-[2-[2-(4-aminopyrazol-1-yl)ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-(4-nitropyrazol-1-yl)ethoxy]ethoxy]ethyl]carbamate (500 mg,1.45 mmol) in MeOH (10 mL) was added Pd/C (220 mg, 10 wt %). The mixturewas stirred at 20° C. for 12 hours under H₂ (15 psi) atmosphere. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (400 mg, 87.6% yield) as red oil. LC-MS(ESI⁺) m/z 315.2 (M+H)⁺.

N5-[1-[2-[2-(2-aminoethoxy)ethoxy]ethyl]pyrazol-4-yl]-1-methyl-N7-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidine-5,7-diamine(Intermediate UT)

Step 1—Tert-butylN-[2-[2-[2-[4-[[1-methyl-7-[(4-morpholinocyclohexyl)amino]pyrazolo[4,3-d]pyrimidin-5-yl]amino]pyrazol-1-yl]ethoxy]ethoxy]ethyl]carbamate

Tert-butyl N-[2-[2-[2-(4-aminopyrazol-1-yl)ethoxy]ethoxy]ethyl]carbamate(300 mg, 954umol, Intermediate US),5-chloro-1-methyl-N-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidin-7-amine(223 mg, 636 umol, Intermediate LK) and TsOH (21.9 mg, 127 umol) weretaken up into a microwave tube in NMP (10 mL). The sealed tube washeated at 150° C. for 2 hours under microwave. On completion, aftercooled to 25° C., the reaction mixture was diluted with water (50 mL)and extracted with DCM (2×80 mL). The combined organic layer wasconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (100 mg, 25% yield) as a whitesolid. LC-MS (ESI⁺) m/z 629.2 (M+H)⁺.

Step2—N5-[1-[2-[2-(2-aminoethoxy)ethoxy]ethyl]pyrazol-4-yl]-1-methyl-N7-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidine-5,7-diamine

To a solution of tert-butylN-[2-[2-[2-[4-[[1-methyl-7-[(4-morpholinocyclohexyl)amino]pyrazolo[4,3-d] pyrimidin-5-yl]amino]pyrazol-1-yl]ethoxy]ethoxy]ethyl]carbamate(80.0 mg, 127 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL). Thereaction mixture was stirred at 25° C. for 14 hours. On completion, thereaction mixture was concentrated in vacuo to give the title compound(70 mg, 97.3%, HCl) as a white solid. LC-MS (ESI⁺) m/z 529.5 (M+H)⁺.

(S)-2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-2-cyclohexylaceticacid (Intermediate UU)

Step 1—Ethyl(S)-2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-2-cyclohexylacetate

To a solution of N-((benzyloxy)carbonyl)-N-methyl-L-alanine (13.04 g, 55mmol) and methyl (S)-2-amino-2-cyclohexylacetate hydrochloride (10.4 g,50 mmol) in DMF (100 mL) was added HATU (24.72 g, 65 mmol) and DIPEA(19.35 g, 150 mmol). The reaction mixture was stirred at roomtemperature for 8 h. Water (300 mL) was then added, and the mixture wasextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine (60 mL), dried over anhydrous Na₂SO₄. The solid was filteredand the filtrate was concentrated under reduced pressure, the resultingresidue was purified by column chromatography on silica gel to give thetitle compound as an oil (18 g, 96% yield). ¹H NMR (400 MHz, CDCl3) δ7.37-7.27 (m, 5H), 5.19 (s, 2H), 4.81 (br s, 1H), 4.49 (dd, J=10.8, 5.3Hz, 1H), 3.72 (s, 3H), 2.88 (s, 3H), 1.76-1.50 (m, 6H), 1.36 (d, J=7.1Hz, 3H), 1.27-1.13 (m, 2H), 1.08-0.90 (m, 3H).

Step2—(S)-2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-2-cyclohexylaceticAcid

To a solution of methyl(S)-2-((S)-2-(((benzyloxy)carbonyl)(methyl)amino)propanamido)-2-cyclohexylacetate(18.0 g, 46.15 mmol) in THF (60 mL) and H₂O (12 mL) was added LiOH (1.44g, 60 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hthen at rt for 4 h. THF was removed under reduced pressure, then themixture was adjusted with critic acid to pH=2˜3, and the mixture wasextracted with EtOAc (3×200 mL). The combined organic layers were washedwith brine (60 mL), dried over anhydrous Na₂SO₄. The solid was filteredand the filtrate was concentrated under reduced pressure to give thetitle compound (14 g, 81% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 12.55 (s,1H), 7.39-7.28 (m, 5H), 5.07 (d, J=9.3 Hz, 2H), 4.69 (br s, 1H),4.10-4.07 (m, 1H), 2.85 (s, 3H), 1.65-1.56 (m, 6H), 1.35-1.28 (m, 3H),1.19-1.08 (m, 5H).

2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl4-methylbenzenesulfonate (Intermediate UV)

To a solution of tert-butyl(2-(2-(2-hydroxyethoxy)ethoxy)ethyl)carbamate (11 g, 44.12 mmol, CAS#139115-92-7) in DCM (100 mL) was added Et₃N (8.91 g, 88.24 mmol), thenTosCl (16.82 g, 88.24 mmol) was added portions at room temperature. Thereaction mixture was stirred at room temperature overnight. The reactionmixture was concentrated under reduced pressure, the resulting residuewas purified by column chromatography on silica gel to give the product2,2-dimethyl-4-oxo-3,8,11-trioxa-5-azatridecan-13-yl4-methylbenzenesulfonate as an oil (17 g, yield 96%). ¹H NMR (400 MHz,CDCl₃) δ 7.81-7.79 (m, 2H), 7.34 (d, J=8.0 Hz, 2H), 4.90 (br s, 1H),4.19-4.16 (m, 2H), 3.72-3.68 (m, 2H), 3.61-3.57 (m, 2H), 3.56-3.53 (m,2H), 3.50 (t, J=5.2 Hz, 2H), 3.29 (t, J=5.1 Hz, 2H), 2.45 (s, 3H), 1.42(s, 9H).

3-[4-[3-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate UX)

Step 1—Tert-butylN-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of tert-butylN-[2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethyl]carbamate (0.500 g,1.51 mmol, Intermediate GZ),3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (170mg, 502 umol, Intermediate HP), CuI (47.8 mg, 251 umol) and Pd(PPh₃)₂Cl₂(176 mg, 251 umol) in DMF (10 mL) was added TEA (916 mg, 9.05 mmol, 1.26mL) in a glove box. Then the resulting mixture was stirred at 80° C. for2 hours. On completion, the mixture was diluted with water (90 mL), thenextracted with EA (2×100 mL). The combined organic layers was dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography to give the title compound (131 mg, 30% yield) asbrown liquid. LC-MS (ESI⁺) m/z 611.1 (M+Na)⁺.

Step 2—Tert-butylN-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture tert-butylN-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (110 mg) in THF (15mL) was added Pd/C (0.04 g, 10 wt %) and Pd(OH)₂/C (0.04 g, 284 umol).The reaction mixture was stirred at 20° C. for 40 hours under H₂ (15psi). On completion, the reaction mixture was filtered through celiteand concentrated in vacuo. The residue was purified by columnchromatography (SiO₂, EA) to give the title compound (100 mg, 59% yield)as brown liquid. LC-MS (ESI⁺) m/z 615.1 (M+Na)⁺

Step3—3-[4-[3-[2-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(0.10 g, 168 umol) in DCM (10 mL) was added HC/dioxane (4 M, 2 mL). Thereaction mixture was stirred at 20° C. for 16 hours. On completion, themixture was concentrated in vacuo. The residue was purified by reverseflash (0.1% FA condition) to give the title compound (25.0 mg, 30%yield) as gray solid. LC-MS (ESI⁺) m/z 493.3 (M+H)⁺.

2-[2-[2-(2-Prop-2-vnoxyethoxy)ethoxy]ethoxy]ethanol (Intermediate UY)

To a mixture of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (20.0 g,102 mmol, 17.7 mL, CAS #25322-68-3) and 3-bromoprop-1-yne (14.7 g, 123mmol) in THF (200 mL) was added TBAI (2.28 g, 6.18 mmol), KI (2.56 g,15.45 mmol) and KOH (5.78 g, 102 mmol). The mixture was stirred at 25°C. for 12 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was purified by column chromatography(PE:EA=5/1 to 0/1) to give the title compound (16.0 g, 67% yield) as alight yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.18 (d, J=2.4 Hz, 2H), 3.70(d, J=4.8 Hz, 2H), 3.67 (d, J=3.2 Hz, 2H), 3.69-3.61 (m, 10H), 3.60-3.57(m, 2H), 2.73 (s, 1H), 2.42 (t, J=2.4 Hz, 1H).

2-[2-[2-[2-[(4-Methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethoxy]ethanamine(Intermediate UZ)

Step 1—Tert-ButylN-[2-[2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (1.65 g, 4.44 mmol, Intermediate AO),1-(4-methoxyphenyl)-N-methyl-methanamine (671 mg, 4.44 mmol) in DMF(20.0 mL) was added K₂CO₃ (1.23 g, 8.88 mmol). The mixture was stirredat 20° C. for 15 hours. On completion, the mixture was diluted with H₂O(60 mL), then extracted with EA (3×30 mL). The organic layers werewashed with brine (3×30 mL) and dried with anhydrous Na₂SO₄, filteredand concentrated in vacuo. The mixture was purified by reverse phase:(0.1% FA) to give the title compound (700 mg, 36% yield) as yellow oil.1H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 6.90 (d,J=8.8 Hz, 2H), 3.87 (s, 2H), 3.83 (s, 3H), 3.81-3.75 (m, 2H), 3.68-3.61(m, 8H), 3.56-3.48 (m, 2H), 3.38-3.25 (m, 2H), 2.96-2.84 (m, 2H), 2.48(s, 3H), 1.46 (s, 9H).

Step2—2-[2-[2-[2-[(4-Methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethoxy]ethanamine

To a solution of tert-butyl N-[2-[2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy] ethoxy]ethyl]carbamate (700 mg, 1.64mmol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 10.0 mL). Themixture was stirred at 15° C. for 0.5 hour. On completion, the mixturewas concentrated in vacuo to give the title compound (590 mg, 90% yield,HCl salt) as yellow oil. LC-MS (ESI⁺) m/z 327.3 (M+H)⁺.

2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione(Intermediate VA)

Step1—2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-[(4-methoxyphenyl)methyl-methylamino]ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of2-[2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethoxy]ethanamine (590 mg, 1.63 mmol, HCl, Intermediate UZ),2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (494 mg, 1.79mmol, Intermediate R) in dioxane (10.0 mL) was added DIPEA (2.10 g, 16.2mmol). The mixture was stirred at 115° C. for 16 hours. On completion,the mixture was concentrated in vacuo. The mixture was purified byreverse phase: (0.1% FA) to give the title compound (500 mg, 52% yield)as yellow solid. LC-MS (ESI⁺) m/z 583.3 (M+H)⁺.

Step2—2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-[2-[(4-methoxyphenyl)methyl-methylamino]ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione (400 mg, 686 umol)in MeOH (10.0 mL) was added Pd/C (200 mg) and Pd(OH)₂/C (200 mg) and HCl(1.00 M, 686 uL). The mixture was stirred at 15° C. for 1 hour under H₂(15 psi). On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The mixture was purified by reverse phase (0.1%HCl) to give the title compound (160 mg, 50% yield) as yellow solid.LC-MS (ESI⁺) m/z 463.3 (M+H)⁺.

3-[4-[3-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate VB)

Step1—3-[4-[3-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethanol(1.03 g, 4.44 mmol, Intermediate UY) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (0.50g, 1.48 mmol, Intermediate HP) in DMSO (20 mL) was added CuI (56.3 mg,295 umol), P(t-Bu)₃ (2.30 g, 1.48 mmol, 2.67 mL, 13% solution oftoluene), DIPEA (955 mg, 7.39 mmol) and Pd(PPh₃)₂Cl₂ (103 mg, 147 umol).The reaction mixture was stirred at 80° C. for 3 hours. On completion,the reaction mixture was diluted with water (60 mL) and extracted withEA (4×60 mL). The combined organic layers was dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The crude productwas purified by prep-HPLC (0.1% FA condition) to give the title compound(0.50 g, 69% yield) as brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s,1), 7.17 (d, J=8.0 Hz, 1H), 7.15-7.11 (m, 1H), 7.06-7.00 (m, 1H), 5.40(dd, J=5.2, 12.8 Hz, 1H), 4.55 (t, J=5.2 Hz, 1H), 4.46 (s, 2H),3.70-3.61 (m, 5H), 3.60-3.57 (m, 2H), 3.53-3.51 (m, 6H), 3.49-3.47 (m,4H), 3.41-3.39 (m, 2H), 2.95-2.84 (m, 1H), 2.77-2.58 (m, 2H), 2.07-1.99(m, 1H).

Step2—3-[4-[3-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(200 mg, 408 umol) in THF (10 mL) was added Pd/C (100 mg, 10% wt) andPd(OH)₂/C (100 mg, 10% wt). The reaction mixture was stirred at 25° C.for 12 hours under H₂ (15 psi) atmosphere. On completion, the reactionmixture was filtrated and concentrated in vacuo to give the titlecompound (180 mg, 89% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 6.96 (d, J=4.4 Hz, 2H), 6.90-6.86 (m, 1H), 5.36 (dd,J=5.2, 12.4 Hz, 1H), 4.57 (t, J=5.2 Hz, 1H), 4.03 (q, J=7.2 Hz, 1H),3.56 (s, 3H), 3.52 (d, J=5.6 Hz, 10H), 3.48-3.45 (m, 4H), 3.40 (d, J=5.2Hz, 2H), 2.98-2.93 (m, 2H), 2.89-2.84 (m, 1H), 2.72-2.63 (m, 2H),2.61-2.58 (m, 2H), 2.02-1.96 (m, 2H), 1.85-1.81 (m, 1H); LC-MS (ESI⁺)m/z 494.3 (M+H)⁺.

2-[[2-[[2-[Benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]acetic Acid (Intermediate VC)

Step 1-Methyl2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetate

To a solution of 2-[benzyloxycarbonyl(methyl)amino]acetic acid (4.30 g,19.2 mmol, CAS #39608-31-6) and methyl 2-(methylamino)acetate (2.69 g,19.2 mmol, HCl, CAS #5473-12-1) in DMF (25 mL) was added DIPEA (4.98 g,38.5 mmol) and HATU (8.79 g, 23.1 mmol). The reaction mixture wasstirred at 25° C. for 1 hours. On completion, the reaction mixture wasquenched with water (100 mL) and extracted with EA (3×200 mL). Thecombined organic layers were washed with brine (2×200 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(5.00 g, 84% yield) as colorless oil. LC-MS (ESI⁺) m/z 309.1 (M+H)⁺.

Step 2—2-[[2-[Benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]aceticacid

To a solution of methyl2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetate (2.00g, 6.49 mmol) in THF (20 mL) and H₂O (4 mL) was added LiOH (310 mg, 12.9mmol). The reaction mixture was stirred at 25° C. for 12 hours. Oncompletion, the reaction mixture was acidified to pH=5 with 1.0 M aq.HCl and concentrated in vacuo. The residue was purified by flash (0.1%,HC) to give the title compound (1.80 g, 91% yield) as colorless oil.LC-MS (ESI⁺) m/z 295.1 (M+H)⁺.

Step 3—Methyl2-[[2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]acetate

To a solution of methyl 2-(methylamino)acetate (1.02 g, 7.34 mmol, HCl,CAS #5473-12-1) and2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetic acid(1.80 g, 6.12 mmol) in DMF (20 mL) was added DIPEA (2.37 g, 18.3 mmol)and HATU (2.56 g, 6.73 mmol). The reaction mixture was stirred at 25° C.for 30 minutes. On completion, the reaction mixture was quenched withwater (30 mL) and extracted with EA (3×100 mL). The combined organiclayers were washed with brine (50 mL), dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by silicacolumn chromatography (PE/EA, 5/1 to 1/1) to give the title compoundcompound (1.30 g, 56% yield) as colorless oil. ¹H NMR (400 MHz,METHANOL-d₄) δ 7.40-7.26 (m, 5H), 5.11 (d, J=17.1 Hz, 2H), 4.44-4.00 (m,6H), 3.81-3.68 (m, 3H), 3.11-2.91 (m, 9H).

Step4—2-[[2-[[2-[Benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]acetic Acid

To a solution of methyl2-[[2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]acetate (1.00 g, 2.64 mmol) in THF (20 mL) and H₂O(4 mL) was added LiOH (126 mg, 5.27 mmol). The reaction mixture wasstirred at 25° C. for 2 hours. On completion, the reaction mixture wasconcentrated in vacuo, diluted with water (30 mL) and acidified to pH=5with 1.0 M aq.HCl. The reaction mixture was concentrated in vacuo. Theresidue was purified by flash (0.1%, HCl) to give the title compound(600 mg, 62% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.41-7.23 (m, 5H), 5.13-5.01 (m, 2H), 4.35-3.88 (m, 5H), 4.35-3.87 (m,1H), 3.04-2.74 (m, 9H).

3-[3-Methyl-4-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate VD)

Step 1—Tert-ButylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-N-methyl-carbamate

To a solution of tert-butyl N-methyl-N-prop-2-ynyl-carbamate (450 mg,2.66 mmol, Intermediate IY) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300mg, 887 umol, Intermediate HP) in DMF (15 mL) was added Cs₂CO₃ (1.45 g,4.44 mmol), CuI (33.7 mg, 177 umol) and Pd(PPh₃)₂Cl₂ (124 mg, 177 umol).The reaction mixture was stirred at 80° C. for 2 hours under N₂. Oncompletion, the mixture was filtered, and the filtrate was concentratedin vacuo. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (200 mg, 58% yield) as yellow solid. LC-MS(ESI⁺) m/z 449.2 (M+Na)⁺.

Step 2—Tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]-N-methyl-carbamate

To a solution of tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-N-methyl-carbamate(220 mg, 515 umol) in THF (20 mL) was added Pd/C (250 mg, 10 wt %) andPd(OH)₂/C (250 mg, 10 wt %). The mixture was stirred at 25° C. under H₂(15 psi) for 2 hours. On completion, the residue was filtered and thefiltrate was concentrated in vacuo to give the title compound (210 mg,94% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),7.00-6.93 (m, 2H), 6.91-6.86 (m, 1H), 5.36 (dd, J=5.2, 12.4 Hz, 1H),3.55 (s, 3H), 3.28-3.21 (m, 2H), 2.91-2.83 (m, 3H), 2.80 (s, 3H),2.75-2.61 (m, 2H), 2.01-1.96 (m, 1H), 1.86-1.72 (m, 2H), 1.36 (s, 9H).LC-MS (ESI⁺) m/z 453.1 (M+Na)⁺.

Step3—3-[3-Methyl-4-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]-N-methyl-carbamate(210 mg, 487 umo) in DCM (3 mL) was added HCl/dioxane (4 M, 3 mL). Themixture was stirred at 25° C. for 2 hours. On completion, the mixturewas concentrated in vacuo to give the title compound (178 mg, 99% yield,HCl) as a white solid. LC-MS (ESI⁺) m/z 331.1 (M+H)⁺.

N-[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-2-(methylamino)acetamide(Intermediate VE)

Step 1—BenzylN-[2-[[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-carbamate

To a solution of3-[3-methyl-4-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(100 mg, 272 umol, HCl, Intermediate VD) and2-[[2-[[2-[benzyloxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]aceticacid (99.6 mg, 272 umol, Intermediate VC) in DMF (5 mL) was HATU (124mg, 327 umol) and DIPEA (176 mg, 1.36 mmol, 237 uL). The mixture wasstirred at 25° C. for 1.5 hours. On completion, the reaction mixture wasdiluted with H₂O (5 mL) and then concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(140 mg, 75% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08(s, 1H), 7.41-7.19 (m, 5H), 7.03-6.81 (m, 3H), 5.36 (dd, J=5.2, 12.4 Hz,1H), 5.10-4.94 (m, 2H), 4.35-4.13 (m, 4H), 4.08-3.85 (m, 2H), 3.61-3.51(m, 3H), 3.46-3.26 (m, 5H), 2.98-2.76 (m, 14H), 2.72-2.59 (m, 2H),2.04-1.71 (m, 3H). LC-MS (ESI⁺) m/z 678.3 (M+H).

Step2—N-[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-2-(methylamino)acetamide

To a solution of benzylN-[2-[[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-carbamate(200 mg, 295 umol) in THF (10 mL) was added Pd/C (100 mg, 915 umol, 10wt %) and Pd(OH)₂/C (100 mg, 915 umol, 10 wt %). The mixture was stirredat 25° C. under H₂ (15 psi) for 12 hours. On completion, the residue wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (140 mg, 87% yield) as a white solid. LC-MS (ESI⁺) m/z 544.3(M+H)⁺.

2-[[2-[[2-[Tert-butoxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]Acetic Acid (Intermediate VF)

Step 1—Methyl2-[[2-[Tert-butoxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetate

To a solution of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (5.00g, 26.4 mmol, CAS #13734-36-6) in THF (25 mL) was added CDI (4.28 g,26.4 mmol) under ice-cooling bath. The resulting mixture was stirred for1 hour; then methyl 2-(methylamino)acetate (3.69 g, 26.4 mmol, HCl) wasadded followed by addition of a solution of TEA (2.94 g, 29.0 mmol, 4.05mL) in THF (20 mL). The resulting mixture was stirred at 20° C. for 20hours. On completion, the mixture was concentrated in vacuo. The residuewas diluted with EA (100 mL), washed with 10% aq. NaHCO₃ and 1 M aq. HClsubsequently; dried with Na₂SO₄ filtered and concentrated in vacuo togive the title compound (3.73 g, 51% yield) as yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ 4.35-4.23 (m, 4H), 3.55-3.45 (m, 3H), 3.05 (s, 3H),2.89-2.93 (m, 3H), 1.47-1.25 (m, 9H).

Step 2—Methyl 2-[methyl-[2-(methylamino)acetyl]amino]acetate

To a solution of methyl2-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetate(3.73 g, 13.60 mmol) in DCM (10 mL) was added TFA (7.70 g, 67.53 mmol, 5mL) under 0° C. The resulting mixture was stirred at 20° C. for 16hours. On completion, the mixture was concentrated in vacuo to give togive the title compound (3.85 g, 98% yield, TFA salt) as yellow oil.

Step 3-Methyl2-[[2-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]acetate

To a solution of 2-[tert-butoxycarbonyl(methyl)amino]acetic acid (1.31g, 6.94 mmol, CAS #13734-36-6) and TEA (3.51 g, 34.7 mmol, 4.83 mL) inTHF (50 mL) was isobutyl carbonochloridate (2.37 g, 17.3 mmol, 2.28 mL,CAS #543-27-1) at 0° C. The mixture was stirred at 25° C. for 0.5 hour,then methyl 2-[methyl-[2-(methylamino)acetyl]amino]acetate (2.00 g, 6.94mmol, TFA) was added, and the mixture was stirred at 25° C. for 3 hours.On completion, the reaction mixture was diluted with H₂O (50 mL), andextracted with EA (2×100 mL), then concentrated in vacuo. The residuewas purified by prep-HPLC (column: Kromasil 150*25 mm*10 um; mobilephase: [water (0.225% FA)-ACN]; B %: 17%-47%, 10 min) to give the titlecompound (400 mg, 16% yield) as yellow oil. ¹H NMR (400 MHz, CD₃Cl) δ4.15-4.12 (m, 3H), 3.78 (s, 1H), 3.82-3.77 (m, 1H), 3.75-3.73 (m, 2H),3.09-3.05 (m, 5H), 2.99-2.95 (m, 2H), 2.92 (s, 3H), 2.95-2.88 (m, 3H),1.46 (s, 9H).

Step4—2-[[2-[[2-[Tert-butoxycarbonyl(methyl]amino]acetyl]-methyl-amino]acetyl]-methyl-amino]aceticAcid

To a solution of methyl 2-[[2-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]-methyl-amino] acetyl]-methyl-amino]acetate (200 mg, 579 umol) inTHF (4 mL) and H₂O (2 mL) was added LiOH (27.7 mg, 1.16 mmol). Thereaction mixture was stirred at 25° C. for 12 hr. On completion, themixture was concentrated in vacuo. The residue was diluted with H₂O (4mL), and then adjusted to pH=5 with 1.0 M aq.HCl to give the titlecompound (190 mg, 99% yield) as yellow oil. LC-MS (ESI⁺) m/z 232.1(M+H)⁺.

3-[3-Methyl-5-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate VG)

Step 1—Tert-ButylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]-N-methyl-carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HN), tert-butylN-methyl-N-prop-2-ynyl-carbamate (400 mg, 2.37 mmol, Intermediate IY)and Pd(PPh₃)₂Cl₂ (83.0 mg, 118 umol) in DMF (4 mL) was added PPh₃ (62.0mg, 236 umol), TEA (2.15 g, 21.2 mmol) and CuI (22.5 mg, 118 umol). Thereaction mixture was stirred at 80° C. for 3 hours under N₂. Oncompletion, the reaction mixture was quenched with aq. NH₄Cl (30 mL) andextracted with EA (3×50 mL). The combined organic layers were washedwith brine (50 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash (0.1%, FA) togive the title compound (200 mg, 37% yield) as a yellow solid. LC-MS(ESI⁺) m/z 427.1 (M+H)⁺.

Step 2—Tert-ButylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]-N-methyl-carbamate

To a solution of tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]-N-methyl-carbamate(200 mg, 468 umol) in THF (20 mL) was added Pd(OH)₂ (25.0 mg, 178 umol)and Pd/C (25.0 mg, 10 wt %). The reaction mixture was stirred at 25° C.for 12 hours under H₂ (15 psi). On completion, the reaction mixture wasdiluted with EA (20 mL), filtered through a short of silica column andwashed with EA (2×50 mL). The organic layers were concentrated in vacuo.The residue was purified by flash chromatography (0.1%, FA) to give thetitle compound (200 mg, 99% yield) as a white solid. LC-MS (ESI⁺) m/z331.0 (M−100+H)⁺.

Step3—3-[3-Methyl-5-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl]-N-methyl-carbamate(200 mg, 464 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 5 mL). Thereaction mixture was stirred at 25° C. for 20 min. On completion, thereaction mixture was concentrate in vacuo to give the title compound(150 mg, 97% yield) as a white solid. LC-MS (ESI⁺) m/z 331.1 (M+H)⁺.

N-[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-2-(methylamino)acetamide(Intermediate VH)

Step 1—Tert-ButylN-[2-[[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-carbamate

To a solution of3-[3-methyl-5-[3-(methylamino)propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(100 mg, 272 umol, HCl, Intermediate VG) and2-[[2-[[2-[tert-butoxycarbonyl(methyl)amino]acetyl]-methyl-amino]acetyl]-methyl-amino]aceticacid (108 mg, 327 umol, Intermediate VF) in DMF (5 mL) was added DIPEA(105 mg, 817 umol) and HATU (124 mg, 327 umol). The reaction mixture wasstirred at 25° C. for 30 mines. On completion, the reaction mixture wasquenched with water (5 mL), concentrated in vacuo. The residue waspurified by flash chromatography (0.1%, FA) to give the title compound(50.0 mg, 28% yield) as a white solid. LC-MS (ESI⁺) m/z 644.2 (M+H)⁺.

Step2—N-[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-2-(methylamino)acetamide

To a solution of tert-butylN-[2-[[2-[[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propyl-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-methyl-amino]-2-oxo-ethyl]-N-methyl-carbamate(50.0 mg, 77.6 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 10mL).The reaction mixture was stirred at 25° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo to give the titlecompound (40.0 mg, 88% yield, HCl) as a white solid. LC-MS (ESI⁺) m/z544.2 (M+H)⁺.

N-[3-carbamoyl-1-(4-formylphenvl)pyrazol-4-yl]-4-cyano-pyridine-2-carboxamide(Intermediate VI)

Step1—N-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-4-cyano-pyridine-2-carboxamide

To a solution of4-amino-1-[4-(hydroxymethyl)phenyl]pyrazole-3-carboxamide (200 mg, 861umol, Intermediate GB) and 4-cyanopyridine-2-carboxylic acid (102 mg,688 umol, CAS #640296-19-1) in DMF (5 mL) was added DIPEA (222 mg, 1.72mmol) and HATU (327 mg, 861 umol). The reaction mixture was stirred at25° C. for 1 hour. On completion, the reaction mixture was poured intowater (10 mL), the solid was filtered and washed with water (2×5 mL).Then the solid was dried in vacuo to give the title compound (200 mg,42% yield) as a white solid. LC-MS (ESI⁺) m/z 385.0 (M+Na)⁺.

Step2—N-[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]-4-cyano-pyridine-2-carboxamide

To a solution ofN-[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]-4-cyano-pyridine-2-carboxamide(130 mg, 358 umol) in THF (10 mL) was added DMP (152 mg, 358 umol) at 0°C. Then the reaction mixture was stirred at 25° C. for 2 hours. Oncompletion, the reaction mixture was filtered. The filtrate wasconcentrated in vacuo to give the title compound (100 mg, 277 umol, 77%yield) as a white solid. LC-MS (ESI⁺) m/z 383.0 (M+Na)⁺.

2-[2-[2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (Intermediate VJ)

To a solution of3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(150 mg, 304 umol, Intermediate VB) in DCM (10 mL) was added TEA (92 mg,911 umol) and MsCl (104 mg, 911 umol). The mixture was stirred at 25° C.for 4 hours. On completion, the mixture was concentrated in vacuo togive the title compound (170 mg, 98% yield) as yellow oil. LC-MS (ESI⁺)m/z 572.3 (M+1)⁺.

3-[4-[3-[2-[2-[2-[2-(4-Amino-1-piperidyl)ethoxy]ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate VK)

Step 1—Tert-ButylN-[1-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl]-4-piperidyl]carbamate

To a solution of2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy] ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (250 mg, 437 umol,Intermediate VJ) in ACN (10 mL) was added KI (7.26 mg, 43 umol), NaHCO₃(110 mg, 1.31 mmol) and tert-butyl N-(4-piperidyl)carbamate (175 mg, 875umol, CAS #73874-95-0). The mixture was stirred at 80° C. for 16 hours.On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by reversed phase flashchromatography to give the title compound (200 mg, 66% yield) as lightyellow oil. LC-MS (ESI⁺) m/z 676.4 (M+1)⁺.

Step2—3-[4-[3-[2-[2-[2-[2-(4-Amino-1-piperidyl)ethoxy]ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[1-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]ethyl]-4-piperidyl]carbamate(200 mg, 295 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 5 mL). Themixture was stirred at 25° C. for 3 hours. On completion, the mixturewas concentrated in vacuo to give the title compound (180 mg, 99% yield)as yellow solid. LC-MS (ESI⁺) m/z 576.4 (M+1)⁺.

[4-(4,5,6,7-Tetrahydropyrazolo[4,3-b]pyridin-2-yl)phenyl]methanol(Intermediate VL)

Step 1—Tert-Butyl2,5,6,7-tetrahydropyrazolo[4,3-b]pyridine-4-carboxylate

To a mixture of 4,5,6,7-tetrahydro-2H-pyrazolo[4,3-b]pyridine (500 mg,3.13 mmol, HCl, CAS #1187830-47-2) and (Boc)₂O (752 mg, 3.45 mmol) inMeOH (15 mL) was added aq.K₂CO₃ (3 M, 2.09 mL). The reaction mixture wasstirred at 20° C. for 15 hours. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography (SiO₂) to give the title compound (500 mg, 71% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.05 (s, 1H), 7.55 (s, 11H),3.66-3.55 (m, 2H), 2.65 (t, J=6.4 Hz, 2H), 1.94-1.82 (m, 2H), 1.51 (s,9H).

Step 2—Tert-Butyl2-[4-(hydroxymethyl)phenyl]-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-carboxylate

To a solution of [4-(hydroxymethyl)phenyl]boronic acid (112 mg, 739umol, CAS #59016-93-2) and tert-butyl2,5,6,7-tetrahydropyrazolo[4,3-b]pyridine-4-carboxylate (110 mg, 493umol) in DCM (5 mL) was added Cu(OAc)₂ (179 mg, 985 umol) and pyridine(2 mL). The reaction mixture was stirred at 25° C. for 12 hours underoxygen (15 psi) atmosphere. On completion, the mixture was quenched withammonia water (20 mL), stirred and separated. The organic layer wasacidified to pH=5 with 1N aq.HCl (20 mL), separated and washed withbrine (20 mL), then concentrated in vacuo. The mixture was purified bysilica gel chromatography (SiO₂) to give the title compound (80.0 mg,49% yield) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (s, 1),7.64 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 4.93 (t, J=5.6 Hz, 1H),4.53 (d, J=5.6 Hz, 2H), 3.72-3.62 (m, 2H), 2.78-2.71 (m, 2H), 2.00-1.91(m, 2H), 1.54 (s, 9H); LC-MS (ESI⁺) m/z 330.2 (M+H)⁺.

Step 3—[4-(4,5,6,7-Tetrahydropyrazolo[4,3-b]pyridin-2-yl)phenyl]methanol

To a solution of tert-butyl2-[4-(hydroxymethyl)phenyl]-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-carboxylate(60.0 mg, 182 umol) in DCM (4 mL) was added HCl/dioxane (4 mL). Thereaction mixture was stirred at 25° C. for 12 hours. On completion, themixture was concentrated in vacuo to give the title compound (45 mg, 93%yield, HCl) as a yellow solid. LC-MS (ESI⁺) m/z 230.1 (M+H)⁺.

Tert-ButylN-[4-[4-[2-(4-formylphenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-carbonyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate VM)

Step 1—Tert-butylN-[4-[4-[2-[4-(hydroxymethyl)phenyl]-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-carbonyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of[4-(4,5,6,7-tetrahydropyrazolo[4,3-b]pyridin-2-yl)phenyl]methanol (45.0mg, 169 umol, HCl, Intermediate VL) and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (52.5 mg, 135 umol, Intermediate CM) in DMF (4 mL) was added HATU(64.4 mg, 169 umol) and DIPEA (109 mg, 847 umol). The reaction mixturewas stirred at 25° C. for 0.5 hour. On completion, the mixture wasquenched with water (50 mL), stirred and filtered. The filter cake wasdried in vacuo to give the title compound (70 mg, 69% yield) as a brownsolid. LC-MS (ESI⁺) m/z 599.3 (M+H)+

Step 2—Tert-butylN-[4-[4-[2-(4-formylphenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-carbonyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[2-[4-(hydroxymethyl)phenyl]-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-carbonyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(70.0 mg, 117 umol) in DCM (4 mL) was added DMP (74.4 mg, 175 umol). Thereaction mixture was stirred at 25° C. for 2 hours. On completion, themixture was quenched with sat.NaHCO₃ (20 mL) and sat. Na₂S₂O₃ (20 mL)and extracted with DCM (2×30 mL). The organic layer was washed withbrine (40 mL), dried over Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to give the title compound (65 mg, 93% yield) as ayellow solid. LC-MS (ESI⁺) m/z 597.3 (M+H)⁺.

(4-Nitrophenyl)N-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl]carbamate(Intermediate VN)

To a solution of tert-butylN-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (500 mg, 2.01 mmol, CAS#153086-78-3), (4-nitrophenyl)carbonochloridate (446 mg, 2.21 mmol) inDCM (20.0 mL) was added TEA (509 mg, 5.03 mmol). The mixture was stirredat 0° C. for 1 hour. On completion, the mixture was concentrated invacuo to give the title compound (800 mg, 90% yield) as yellow solid.LC-MS (ESI⁺) m/z 314.1 (M+H−100)⁺.

1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea(Intermediate VO)

Step 1—Tert-ButylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)--oxo-isoindolin-5-yl]methylcarbamoylamino]ethoxy]ethoxy]ethyl]carbamate

To a solution of3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (130 mg,419 umol, HCl, Intermediate QM),(4-nitrophenyl)N-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl]carbamate(347 mg, 839 umol, Intermediate VN) in DMF (15.0 mL) was added TEA (212mg, 2.10 mmol). The mixture was stirred at 20° C. for 1 hour. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by reverse phase chromatography (0.1% FA) to give the titlecompound (170 mg, 73% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.99 (s, 1H), 7.67 (d, J=7.6 Hz, 1), 7.45 (s, 1), 7.38 (d, J=7.6 Hz,1), 6.78 (s, 1), 6.56 (t, J=6.0 Hz, 1H), 6.04 (t, J=5.6 Hz, 1H),5.16-5.05 (m, 1H), 4.47-4.24 (m, 4H), 3.53-3.36 (m, 8H), 3.24-3.13 (m,2H), 3.10-3.02 (m, 2H), 2.99-2.85 (m, 1H), 2.65-2.55 (m, 1H), 2.46-2.36(m, 1H), 2.05-1.94 (m, 1H), 1.37 (s, 9H).

Step2—1-[2-[2-(2-Aminoethoxy)ethoxy]ethyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea

To a solution of tert-butylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methylcarbamoylamino]ethoxy]ethoxy]ethyl]carbamate(170 mg, 310 umol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 8.00mL). The mixture was stirred at 15° C. for 0.5 hour. On completion, themixture was concentrated in vacuo to give the title compound (150 mg,90% yield, HCl) as white solid. LC-MS (ESI⁺) m/z 448.1 (M+H)⁺.

Methyl 5-[4-amino-3-(difluoromethyl)pyrazol-1-yl]pyridine-2-carboxylate(Intermediate VP)

Step 1—Methyl5-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]pyridine-2-carboxylate

To a solution of 3-(difluoromethyl)-4-nitro-1H-pyrazole (200 mg, 1.23mmol, Intermediate HS), (6-methoxycarbonyl-3-pyridyl)boronic acid (266mg, 1.47 mmol, CAS #1072945-86-8) in DCM (20 mL) was added Cu(OAc)₂ (334mg, 1.84 mmol) and pyridine (388 mg, 4.91 mmol). The mixture was stirredat 15° C. for 6 hrs under O₂ (15 psi). On completion, the mixture washedwith NH₃H₂O (100 mL) and then the layers were washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue wastriturated with PE:EA=1:1 (50 mL) and filtered. The filtered cake wasdried in vacuo to give the title compound (100 mg, 27% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.23-9.08 (m, 1H), 8.85 (s, 1),8.35 (s, 2H), 7.26-7.06 (t, J=5.2 Hz, 1), 4.08 (s, 3H).

Step 2—Methyl 5-[4-amino-3-(difluoromethyl)pyrazol-1-yl]-2-carboxylate

To a solution of methyl5-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]pyridine-2-carboxylate (100mg, 335 umol) in DCM (10 mL) was added Pd/C (50.0 mg, 50 wt %). Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (15 psi) at 15° C. for 2 hours. Oncompletion, the mixture was filtered through celite. The filtrate wasconcentrated in vacuo to give the title compound (89.0 mg, 332 umol, 99%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (d, J=2.0 Hz,1H), 8.32-8.29 (m, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.29-6.97 (t, J=5.2 Hz,1H), 8.00 (s, 1H), 3.91 (s, 3H), 4.62 (s, 2H).

5-[4-[[2-[2-[Tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]pyridine-2-carboxylicAcid (Intermediate YQ)

Step 1—Methyl5-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]pyridine-2-carboxylate

To a solution of methyl5-[4-amino-3-(difluoromethyl)pyrazol-1-yl]pyridine-2-carboxylate (0.300g, 1.12 mmol, Intermediate VP) and2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (402 mg, 1.12 mmol, Intermediate OM) in DMF (2 mL) was added HATU(510 mg, 1.34 mmol) and DIPEA (361 mg, 2.80 mmol). The mixture wasstirred at 15° C. for 2 hrs. On completion, to the mixture was addedinto H₂O and a precipitate formed. The mixture was filtered and thefilter cake was dried in vacuo to give the title compound (50.0 mg, 820umol, 73% yield) as a yellow solid. LC-MS (ESI⁺) m/z 610.3 (M+H)⁺.

Step2—5-[4-[[2-[2-[Tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]pyridine-2-carboxylic acid

To a solution of methyl5-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]pyridine-2-carboxylate(500 mg, 820 umol) in THF (50 mL), H₂O (50 mL) and MeOH (10 mL) wasadded LiOH·H₂O (172 mg, 4.10 mmol). The mixture was stirred at 15° C.for 6 hrs. On completion, the mixture was adjusted to pH-6-7 with 1.0 Maq.HCl and a precipitate formed. The mixture was filtered and the filtercake was dried in vacuo to give the title compound (500 mg, 90% yield,90% purity) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H)9.28 (d, J=2.4 Hz, 1H) 9.07 (s, 2H) 8.60 (d, J=5.2 Hz, 1H) 8.44-8.52 (m,1H) 8.32 (s, 1H) 8.18-8.25 (m, 1H) 7.64-7.78 (m, 1H) 7.19-7.52 (m, 1H)1.52 (s, 9H) 1.09-1.28 (m, 1H) 0.35-0.50 (m, 2H) 0.24 (q, J=4.8 Hz, 2H);LC-MS (ESI⁺) m/z 596.2 (M+H)⁺.

3-[5-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate VR)

Step 1—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (250mg, 739 umol, Intermediate HN) and tert-butylN-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (540 mg, 2.22 mmol,synthesized via Step 1 of Intermediate CQ) in DMSO (10 mL) was added CuI(28.2 mg, 148 umol), DIPEA (478 mg, 3.70 mmol) and Pd(PPh₃)₂Cl₂ (104 mg,148 umol). The mixture was stirred at 80° C. for 2 hrs in a glove box.On completion, the reaction mixture was purified by reverse phasechromatography (0.1% FA condition) to give the title compound (140 mg,35% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H),7.33 (s, 1H), 7.22-7.09 (m, 2H), 6.86-6.71 (m, 1H), 5.42-5.37 (m, 1H),4.40 (s, 2H), 3.67-3.61 (m, 2H), 3.59-3.53 (m, 2H), 3.08 (m, 2H),2.95-2.86 (m, 1H), 2.08-2.00 (m, 1H), 1.37 (s, 9H). LC-MS (ESI⁺) m/z506.3 (M+4)⁺.

Step 2—Tert-ButylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethyl]carbamate (120 mg, 240 umol) in THF (20 mL)was added Pd/C (50 mg, 50 wt %) and Pd(OH)₂/C (50 mg, 10 wt %) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred under H₂ (15 psi) at 15° C. for 2 hours.On completion, the mixture was filtered through celite. The filtrate wasconcentrated in vacuo to give the title compound (100 mg, 80% yield) asa yellow solid. LC-MS (ESI⁺) m/z 505.3 (M+H)⁺.

Step3—3-[5-[3-[2-(2-Aminoethoxy)ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethyl]carbamate (100 mg, 198 umol) in DCM (10 mL) wasadded HCl/dioxane (4 M, 5 mL). The mixture was stirred at 15° C. for 0.5hr. On completion, the mixture was concentrated in vacuo to give thetitle compound (80.0 mg, 95% yield) as a yellow solid. LC-MS (ESI⁺) m/z405.2 (M+H)⁺.

Tert-Butyl N-[2-[2-(2-prop-2-vnoxyethoxy)ethoxy]ethyl]carbamate(Intermediate VS)

A mixture of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate(3.00 g, 12.0 mmol), 3-bromoprop-1-yne (1.72 g, 14.4 mmol, 1.24 mL),TBAI (356 mg, 962 umol), KI (299 mg, 1.81 mmol) and KOH (675 mg, 12.0mmol) in THF (30 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at 25° C. for 16 hrs under N₂ atmosphere.On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (2.50 g, 72% yield) as lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.05 (s, 1H), 4.22 (d, J=2.4 Hz,2H), 3.76-3.60 (m, 8H), 3.55 (t, J=5.2 Hz, 2H), 3.35-3.27 (m, 2H), 2.44(t, J=2.4 Hz, 1H), 1.47 (s, 9H).

3-[5-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate VT)

Step 1—Tert-ButylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate

A mixture of tert-butylN-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]carbamate (849 mg, 2.96 mmol,Intermediate VS),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HN), Pd(PPh₃)₂Cl₂ (311 mg, 443 umol), CuI(84 mg, 443 umol) and TEA (2.69 g, 26.6 mmol, 3.70 mL) in DMF (15 mL)was degassed and purged with N₂ for 3 times, and then the mixture wasstirred at 80° C. for 3 hrs under N₂ atmosphere. On completion, themixture was concentrated in vacuo to give a residue. The residue waspurified by reverse phase chromatography (0.1% FA) to give the titlecompound (400 mg, 49% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.12 (s, 1H), 7.33 (s, 1H), 7.21-7.12 (m, 2H), 6.77-6.71 (m,1H), 5.39 (dd, J=5.2, 12.8 Hz, 1H), 4.40 (s, 2H), 3.68-3.62 (m, 2H),3.61-3.56 (m, 2H), 3.55-3.47 (m, 6H), 3.35 (s, 3H), 3.07 (q, J=6.0 Hz,2H), 2.96-2.80 (m, 1H), 2.72-2.58 (m, 2H), 2.08-1.99 (m, 1H), 1.37 (s,9H).

Step 2—Tert-ButylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate(400 mg, 734 umol) in THF (100 mL) was added Pd/C (300 mg, 10 wt %) andPd(OH)₂/C (300 mg, 10 wt %). The mixture was stirred at 20° C. for 4 hrsunder H₂ (15 psi) atmosphere. On completion, the mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(270 mg, 67% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.07 (s, 1H), 7.08-6.96 (m, 2H), 6.87 (d, J=7.2 Hz, 1H), 6.73 (s, 1H),5.34 (dd, J=5.2, 12.4 Hz, 1H), 3.69-3.35 (m, 15H), 3.09-3.01 (m, 2H),2.97-2.81 (m, 1H), 2.77-2.57 (m, 4H), 2.08-1.94 (m, 1H), 1.89-1.71 (m,2H), 1.37 (s, 9H).

Step3—3-[5-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate(270 mg, 492 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 5 mL). Themixture was stirred at 25° C. for 3 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (220 mg, 92% yield) aslight yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.86 (s,3H), 7.07-6.97 (m, 2H), 6.91-6.84 (m, 1H), 5.40-5.29 (m, 1H), 3.61 (t,J=5.2 Hz, 2H), 3.59-3.56 (m, 4H), 3.55-3.53 (m, 2H), 3.52-3.48 (m, 2H),3.43-3.40 (m, 2H), 3.33 (s, 3H), 3.02-2.84 (m, 3H), 2.76-2.58 (m, 4H),2.05-1.97 (m, 1H), 1.87-1.73 (m, 2H).

3-[4-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate VU)

Step 1—Tert-ButylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate

A mixture of tert-butylN-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethyl]carbamate (1.27 g, 4.44 mmol,Intermediate VS),3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP), CuI (85 mg, 446 umol), Pd(PPh₃)₂Cl₂(311 mg, 443 umol) and Cs₂CO₃ (2.41 g, 7.39 mmol) in DMF (12 mL) wasstirred at 80° C. for 2 hours under N₂ atmosphere. On completion, aftercooled to 25° C., the mixture was filtered through a pad of celite andthe cake was washed with EA (50 mL). The filtrate and washing werecombined, diluted with water (100 mL), and extracted with EA (3×40 mL).The combined organic layer was washed with brine (10 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byreversed phase chromatography (0.1% FA condition) to give the titlecompound (420 mg, 52% yield) as light yellow gum. ¹H NMR (400 MHz,DMSO-d₆) δ 11.11 (s, 1), 7.17 (d, J=8.0 Hz, 1), 7.10-7.15 (m, 1),7.00-7.06 (m, 1), 5.39 (dd, J=12.4, 5.6 Hz, 1H), 4.46 (s, 2H), 3.61-3.69(m, 5H), 3.55-3.60 (m, 2H), 3.46-3.55 (m, 6H), 3.05 (q, J=6.0 Hz, 2H),2.83-2.93 (m, 1H), 2.58-2.76 (m, 3H), 2.04-2.02 (m, 1H), 1.36 (s, 9H).

Step 2—Tert-ButylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethyl]carbamate (500 mg, 918 umol) in THF (10mL) was added Pd/C (200 mg, 918 umol, 10 wt %) and Pd(OH)₂ (200 mg, 1.42mmol). The mixture was stirred at 25° C. for 16 hours under H₂ (15 psi).On completion, the mixture was filtered through a pad of celite, and thecake was washing with EA (20 mL). The filtrate and washing were combinedand concentrated in vacuo to give the title compound (500 mg, 90% yield)as light yellow gum. LC-MS (ESI⁺) m/z 549.2 (M+H)⁺.

Step3—3-[4-[3-[2-[2-(2-Aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate (100 mg, 182 umol) in DCM (2 mL)was added HCl/dioxane (4 M, 4.00 mL). The reaction mixture was stirredat 25° C. for 1 hour. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (100 mg, 98% yield,HCl) as light yellow solid. LC-MS (ESI⁺) m/z 449.3 (M+H)⁺.

Tert-butyl 2-(2-allyloxyethoxy)acetate (Intermediate VV)

To a mixture of 2-allyloxyethanol (3.00 g, 29.3 mmol) anddiacetoxyrhodium (520 mg, 1.18 mmol) in DCM (30 mL) was added a solutionof tert-butyl 2-diazoacetate (12.5 g, 88.1 mmol, CAS #35059-50-8) in DCM(30 mL) at 25° C. dropwise during 2 hours. The mixture was stirred at25° C. for 16 hours under N₂. On completion, to the mixture was addedHOAc (5.0 mL). Then, the mixture was stirred at 25° C. for 0.5 hour. Themixture was concentrated in vacuo. The residue was purified by columnchromatography over silica gel to give the title compound (6.80 g, 100%yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.00-5.85 (m, 1H),5.29 (dd, J=17.2, 2.0 Hz, 1H), 5.19 (dd, J=10.4, 1.6 Hz, 1H), 4.07-4.02(m, 4H), 3.77-3.71 (m, 2H), 3.67-3.59 (m, 2H), 1.49 (s, 9H).

2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]aceticAcid (Intermediate VW)

Step 1—Tert-Butyl2-[2-[(E)-3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]allyloxy]ethoxy]acetate

A mixture of tert-butyl 2-(2-allyloxyethoxy)acetate (1.50 g, 4.62 mmols,Intermediate VV),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg, 1.77 mmol, Intermediate HN), Pd₂(dba)₃ (168 mg, 183 umol), t-Bu₃P(720 mg, 355 umol, 10 wt %) and DIPEA (468 mg, 3.62 mmol) in dioxane (30mL) was stirred at 25° C. for 16 hours under N₂. On completion, themixture was filtered. The filtrate was concentrated in vacuo. Theresidue was purified by reversed phase (0.1% FA condition) to give thetitle compound (500 mg, 59% yield) as light yellow oil. LC-MS (ESI⁺) m/z496.1 (M+Na)⁺.

Step 2—Tert-Butyl2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]acetate

A mixture of tert-butyl2-[2-[(E)-3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]allyloxy]ethoxy]acetate(500 mg), Pd/C (200 mg, 10 wt %) and Pd(OH)₂ (200 mg, 1.42 mmol) in THF(10 mL) was stirred at 25° C. for 16 hours under H₂ (15 psi). Oncompletion, the mixture was filtered, and the cake was washed with EA(20 mL). The filtrate and washings were combined and concentrated invacuo. The residue was purified by reversed phase (0.10% FA condition)to give the title compound (400 mg) as light yellow oil. ¹H NMR (400MHz, CDCl₃) δ 8.14 (s, 1H), 6.93-6.87 (m, 2H), 6.72 (d, J=8.0 Hz, 1H),5.25-5.20 (m, 1H), 4.05 (s, 2H), 3.75-3.72 (m, 2H), 3.66-3.62 (m, 2H),3.49 (t, J=6.4 Hz, 2H), 3.45 (s, 3H), 2.96-2.83 (m, 2H), 2.76-2.71 (m,2H), 2.29-2.19 (m, 2H), 1.95-1.90 (m, 2H) 1.49 (s, 9H).

Step 3—2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]aceticAcid

To a solution of tert-butyl 2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]acetate (400 mg, 815 umol) in DCM (4 mL) was added TFA (4mL) at 25° C. The mixture was stirred at 25° C. for 16 hours. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by reverse phase flash (0.1% TFA condition) to give the titlecompound (180 mg, 42% yield) as light yellow gum. ¹H NMR (400 MHz,CDCl₃) δ 8.35 (s, 1H), 6.94-6.87 (m, 2H), 6.74 (d, J=8.0 Hz, 1H),5.26-5.22 (m, 1H), 4.18 (s, 2H), 3.81-3.74 (m, 2H), 3.64-3.62 (m, 2H),3.55 (t, J=6.4 Hz, 2H), 3.44 (s, 3H), 2.92-2.72 (m, 6H), 2.29-2.19 (m,1H), 2.00-1.90 (m, 2H).

Methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoate(Intermediate VX)

Step 1—Methyl4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-2-fluoro-benzoate

To a solution of 3-(difluoromethyl)-4-nitro-1H-pyrazole (1.00 g, 6.13mmol, Intermediate HS) and (3-fluoro-4-methoxycarbonyl-phenyl)boronicacid (1.58 g, 7.97 mmol, CAS #3505083-04-5) in DCM (20 mL) was addedCu(OAc)₂ (2.23 g, 12.3 mmol) and pyridine (10 mL). The reaction mixturewas stirred at 25° C. for 12 hrs under oxygen (15 psi) atmosphere. Oncompletion, the mixture was quenched with ammonia water (30 mL), thenthe mixture was stirred and separated. The organic layer was acidifiedwith 1N HCl (20 mL) to pH<5, separated and washed with brine (20 mL),concentrated in vacuo. The residue was purified by silica gelchromatography (SiO₂), and then triturated with PE/EA=10/1 (50 mL),filtered and the filter cake was concentrated in vacuo to give the titlecompound (360 mg, 19% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.92 (s, 1H), 8.16-8.04 (m, 2H), 8.02-7.94 (m, 1H), 7.61-7.30 (m, 1H),3.89 (s, 3H).

Step 2—Methyl4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoate

To a solution of methyl4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]-2-fluoro-benzoate (350 mg,1.11 mmol) in THF (10 mL) was added Pd/C (0.1 g, 10% wt). The reactionmixture was stirred at 25° C. for 10 hrs under H₂ (15 psi) atmosphere.On completion, the mixture was concentrated in vacuo to give the titlecompound (310 mg, 98% yield) as a white solid. LC-MS (ESI⁺) m/z 286.1(M+H)⁺.

4-[4-[[2-[2-[Tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoicacid (Intermediate VY)

Step 1—Methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoate

To a solution of methyl4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoate (310 mg,1.09 mmol, Intermediate VX) and2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (391 mg, 1.09 mmol, Intermediate OM) in DMF (6.00 mL) was addedHATU (496 mg, 1.30 mmol) and DIPEA (421 mg, 3.26 mmol). The reactionmixture was stirred at 20° C. for 0.5 hr. On completion, the mixture wasquenched with water (50 mL), and filtered. The filter cake was dried invacuo to give the title compound (600 mg, 88% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H), 9.06 (s, 1H), 9.01 (s, 1H),8.60 (d, J=5.2 Hz, 1), 8.32 (s, 1H), 8.06 (t, J=8.4 Hz, 1H), 8.00-7.94(m, 1), 7.94-7.88 (m, 1), 7.75-7.66 (m, 1H), 7.46-7.16 (m, 1H), 3.88 (s,3H), 3.86 (s, 2H), 1.52 (s, 9H), 1.22-1.12 (m, 1H), 0.45-0.37 (m, 2H),0.28-0.21 (m, 2H); LC-MS (ESI⁺) m/z 627.0 (M+H)⁺.

Step2—4-[4-[[2-[2-[Tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoic Acid

To a mixture of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoate(600 mg, 958 umol) in a mixed solvent of THF (10 mL) and H₂O (2 mL) wasadded LiOH H₂O (160 mg, 3.83 mmol). The reaction mixture was stirred at25° C. for 10 hrs. On completion, the mixture was concentrated in vacuoto remove the THF. The residue was diluted with water (30 mL), acidifiedwith 1N HCl to pH=3-5, filtered and the filter cake was dried in vacuoto give the title compound (570 mg, 97% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 10.15 (s, 1H), 9.15-8.95 (m, 2H), 8.60 (d, J=5.2Hz, 1H), 8.32 (s, 1H), 8.03 (t, J=8.0 Hz, 1H), 7.94-7.83 (m, 2H), 7.71(d, J=4.8 Hz, 1H), 7.47-7.15 (m, 1H), 3.87 (d, J=6.8 Hz, 2H), 1.52 (s,9H), 0.80-0.69 (m, 1H), 0.49-0.36 (m, 2H), 0.29-0.15 (m, 2H); LC-MS(ESI⁺) m/z 613.2 (M+H)⁺.

Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(3-fluoro-4-formyl-phenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (IntermediateVZ)

Step 1—Isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoate

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoicacid (1.00 g, 1.63 mmol, Intermediate VY) and TEA (413 mg, 4.08 mmol) inTHF (30 mL) was added isopropyl carbonochloridate (400 mg, 3.27 mmol)dropwise. The reaction mixture was stirred at 0° C. for 2 hrs. Oncompletion, the mixture was filtered and the filtrate was used for thenext step directly without further purification. LC-MS (ESI⁺) m/z 699.0(M+H)⁺.

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[3-fluoro-4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]-2-fluoro-benzoate(1.14 g, 1.63 mmol) in a mixed solvent of THF (60 mL) and H₂O (1 mL) wasadded LiBH₄ (178 mg, 8.16 mmol). The reaction mixture was stirred at 0°C. for 2 hrs. On completion, the mixture was quenched with water (50mL), then extracted with EA (2×50 mL). The organic layers were washedwith brine (50 mL), dried over Na₂SO₄, and concentrated in vacuo. Theresidue was triturated with DCM/PE=1/10 (50 mL), filtered and the filtercake was dried in vacuo to give the title compound (0.91 g, 93% yield)as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.05 (s,1H), 8.87 (s, 1), 8.60 (d, J=5.1 Hz, 1H), 8.32 (s, 1H), 7.80-7.68 (m,3H), 7.61 (t, J=8.4 Hz, 1H), 7.30 (t, J=54.3, Hz, 1H), 5.37 (t, J=5.7Hz, 1), 4.58 (d, J=5.7 Hz, 2H), 3.86 (d, J=7.2 Hz, 2H), 1.51 (s, 9H),1.20-1.10 (m, 1H), 0.44-0.37 (m, 2H), 0.27-0.20 (m, 2H); LC-MS (ESI⁺)m/z 599.2 (M+H)⁺.

Step 3—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(3-fluoro-4-formyl-phenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[3-fluoro-4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(0.91 g, 1.52 mmol) in DCM (20 mL) was added DMP (774 mg, 1.82 mmol).The reaction mixture was stirred at 25° C. for 10 hrs. On completion,the mixture was quenched with Na₂S₂O₃ (30 mL) and NaHCO₃ (30 mL),stirred for 10 minutes, then extracted with DCM (2×30 mL). The organiclayers were washed with brine (50 mL), dried with Na₂SO₄, filtered andthe filtrate was concentrated in vacuo. The residue was triturated withPE/DCM (10/1, 50 mL), filtered and the filter cake was dried in vacuo togive the title compound (840 mg, 93% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 10.20 (s, 1H), 9.07 (s, 1H), 9.05(s, 1), 8.59 (d, J=5.2 Hz, 1), 8.31 (s, 1), 8.06-7.91 (m, 3H), 7.70 (dd,J=1.2, 5.2 Hz, 1), 7.35 (t, J=107.6 Hz, 1), 3.86 (d, J=6.8 Hz, 2H), 1.52(s, 9H), 1.21-1.14 (m, 1), 0.44-0.38 (m, 2H), 0.28-0.20 (m, 2H); LC-MS(ESI⁺) m/z 597.2 (M+H)⁺.

2—Methyl 4-amino-1-methyl-pyrazole-3-carboxylate (Intermediate WA)

To a mixture of methyl 2-methyl-4-nitro-pyrazole-3-carboxylate (0.5 g,2.70 mmol, synthesized via Step 1 of Intermediate LK) in MeOH (20 mL)was added Pd/C (300 mg, 10% wt). The reaction mixture was stirred at 25°C. for 12 hours under H₂ (15 psi) atmosphere. On completion, thereaction mixture was filtered and concentrated in vacuo to give thetitle compound (400 mg, 95% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 7.12 (s, 1H), 4.67 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H).

1-4-[[5-(4-Tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-1-methyl-pyrazole-3-carboxylicacid (Intermediate WB)

Step 1—Tert-butyl4-[3-[(3-methoxycarbonyl-1-methyl-pyrazol-4-yl)carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate

To a mixture of methyl 4-amino-1-methyl-pyrazole-3-carboxylate (232 mg,1.50 mmol, Intermediate WA) and5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (400 mg, 1.15 mmol, Intermediate RC) in ACN (10 mL) was added DIPEA(446 mg, 3.45 mmol, 601 uL) and HATU (875 mg, 2.30 mmol). The reactionmixture was stirred at 60° C. for 12 hours. On completion, the reactionmixture was concentrated in vacuo. The residue was purified by prep-HPLC(0.1% FA condition) to give the title compound (250 mg, 44% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.80 (d, J=8.0Hz, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 6.88 (d, J=8.0 Hz, 1H), 4.02-3.92(m, 7H), 3.86 (s, 3H), 3.61-3.49 (m, 4H), 1.42 (s, 9H).

Step2—1-4-[[5-(4-Tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-1-methyl-pyrazole-3-carboxylicacid

To a mixture of tert-butyl4-[3-[(3-methoxycarbonyl-1-methyl-pyrazol-4-yl)carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (200 mg, 412 umol) in asolution of THF (10 mL), MeOH (2 mL) and H₂O (2 mL) was added LiOH (98.8mg, 4.13 mmol). The reaction mixture was stirred at 25° C. for 12 hours.On compound, the reaction mixture was acidified with HCl (1 N) untilpH=5-6, then the mixture was concentrated in vacuo to give the titlecompound (194 mg, 99% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.53 (s, 1H), 8.76 (d, J=7.2 Hz, 1H), 8.28 (d, J=17.6 Hz, 2H), 6.85 (d,J=7.6 Hz, 1H), 4.12-3.87 (m, 4H), 3.86 (s, 3H), 3.55-3.49 (m, 4H), 1.43(s, 9H).

Methyl 5-(4-amino-1-methyl-pyrazol-3-yl) pyridine-3-carboxylate(Intermediate (WC)

Step 1—3-Bromo-4-nitro-1H-pyrazole

To a solution of 3-bromo-1H-pyrazole (10 g, 68.0 mmol) in H₂SO₄ (50 mL)was added HNO₃ (10.7 g, 170 mmol) at 0˜10° C. Then, the mixture wasstirred at 80° C. for 2 hours. On completion, the mixture was cooled to25° C. Then, the mixture was poured into ice/water (300 mL), thenextracted with EA (3×150 mL). The combined organic layer was washed withsat. aq. NaHCO₃ (100 mL) and brine (100 mL), dried over Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to give the titlecompound (11.2 g, 85% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.94 (s, 1H).

Step 2—3-Bromo-1-methyl-4-nitro-pyrazole

To a mixture of 3-bromo-4-nitro-1H-pyrazole (6.20 g, 32.3 mmol) andK₂CO₃ (5.36 g, 38.7 mmol) in DMF (40 mL) was added MeI (5.50 g, 38.7mmol) at 0° C. Then, the mixture was stirred at 25° C. for 2 hours. Oncompletion, the mixture was diluted with water (200 mL), then extractedwith EA (3×80 mL). The combined organic layer was washed with brine (50mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by column chromatography over silica gel (PE:EA- 20:1-3:1)to give the title compound (3.90 g, 58% yield) as light yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 3.97 (s, 3H).

Step 3—Methyl 5-(1-methyl-4-nitro-pyrazol-3-yl) pyridine-3-carboxylate

A mixture of 3-bromo-1-methyl-4-nitro-pyrazole (3.80 g, 18.4 mmol),(5-methoxycarbonyl-3-pyridyl)boronic acid (4.67 g, 25.8 mmol, CAS#871329-53-2), Pd(dppf)Cl₂·CH₂Cl₂ (800 mg, 979 umol) and NaHCO₃ (3.10 g,36.8 mmol) in dioxane (50 mL) and H₂O (10 mL) was stirred at 80° C.under N₂ for 2 hours. On completion, the mixture was cooled to 25° C.The mixture was diluted with water (100 mL), then extracted with EA(3×80 mL). The combined organic layer was washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (PE:EA=5:1-DCM:EA=2:1)to give the title compound (2.95 g, 61% yield) as light yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 9.29 (s, 1H), 9.12 (s, 1H), 8.68 (s, 1H), 8.31(s, 1H), 4.05 (s, 3H), 4.00 (s, 3H).

Step 4—Methyl 5-(4-amino-1-methyl-pyrazol-3-yl) pyridine-3-carboxylate

A mixture of methyl5-(1-methyl-4-nitro-pyrazol-3-yl)pyridine-3-carboxylate (2.90 g, 11.0mmol) and Pd/C (500 mg, 11.0 mmol, 10% wt) in DCM (80 mL) and MeOH (40mL) was stirred at 25° C. for 6 hours under H₂ (15 psi). On completion,the mixture was filtered, and the cake was washed with MeOH (50 mL). Thefiltrate and washing were combined and concentrated in vacuo. Theresidue was purified by reversed phase flash (NH₃H₂O condition) to givecrude product (1.8 g). The crude product was purified by prep-HPLC(column: Xbridge BEH C18, 250*50 mm, 10 um; mobile phase: [water (0.05%ammonia hydroxide v/v)-ACN]; B %: 1%-26%, 32 MIN; 45% min) to give thetitle compound (470 mg, 18% yield) as light yellow solid. ¹H NMR (400MHz, CDCl₃) δ 9.23 (d, J=1.6 Hz, 1H), 9.13 (d, J=1.6 Hz, 1), 8.70 (t,J=1.6 Hz, 1), 7.10 (s, 1), 3.97 (s, 3H), 3.88 (s, 3H).

5-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazol-3-yl]pyridine-3-carboxylicAcid (Intermediate WD)

Step1—5-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazol-3-yl]pyridine-3-carboxylate

A mixture of methyl5-(4-amino-1-methyl-pyrazol-3-yl)pyridine-3-carboxylate (90.0 mg, 387umol, Intermediate WC),2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (153 mg, 395 umol, Intermediate CM), HATU (192 mg, 504 umol) andDIPEA (101 mg, 781 umol) in DMF (3 mL) was stirred at 25° C. for 1 hour.On completion, the mixture was combined with another identical batch.The combined mixture quenched with water (1 mL) and purified by reversephase flash (FA condition) to give the title compound (200 mg, 86%yield) as light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.24 (s, 1),9.18 (d, J=1.6 Hz, 1H), 8.83 (s, 1H), 8.69 (s, 1H), 8.51 (d, J=4.8 Hz,1H), 8.42 (s, 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.73 (d, J=5.2 Hz, 1H),4.88 (q, J=8.8 Hz, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 1.55 (s, 9H).

Step2—5-[4-[[2-[2-[Tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazol-3-yl]pyridine-3-carboxylic acid

To a solution of methyl5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazol-3-yl]pyridine-3-carboxylate(200 mg, 332 umol) in THF (6 mL) was added a solution of LiOH·H₂O (21mg, 500 umol) in H₂O (2 mL) at 25° C. Then, the mixture was stirred at25° C. for 16 hours. On completion, the reaction mixture was quenchedwith TFA (60 mg). The mixture was concentrated in vacuo. The residue waspurified by reversed phase flash (TFA condition) to give the titlecompound (190 mg, 81% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 13.47 (s, 1H), 10.11 (s, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.98(s, 2H), 8.64 (d, J=5.2 Hz, 1H), 8.54 (s, 1H), 8.30 (s, 1H), 8.03 (s,1H), 7.80 (d, J=5.2 Hz, 1H), 4.89 (q, J=9.2 Hz, 2H), 3.95 (s, 3H), 1.50(s, 9H).

BenzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(Intermediate WE)

Step 1—Benzyl((S)-1-(((S)-1-((S)-7-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate

To a solution of benzyl((S)-1-(((S)-1-((S)-7-hydroxy-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.6 g, 2.45 mmol, Intermediate PE) in CH₃CN (75 mL) was added2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl4-methylbenzenesulfonate (1.57 g, 2.94 mmol, Intermediate 00) and K₂CO₃(507.2 mg, 3.68 mmol) at rt. Then the reaction mixture was stirred at80° C. for 12 h. The solid was then filtered, and the filtrate wasconcentrated under reduced pressure. The residue was purified via columnchromatography (DCM/MeOH) to give the title compound (1.58 g, 61% yield)as a colorless oil. LC-MS (ESI⁺): m/z 510.01 (M+H)⁺.

Step 2—Benzyl((S)-1-(((S)-1-((S)-7-((17-amino-3,6,9,12,15-pentaoxaheptadecyl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate2,2,2-trifluoroacetate

To a solution of benzyl((S)-1-(((S)-1-((S)-7-((2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azadocosan-22-yl)oxy)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate(1.3 g, 1.28 mmol) in DCM (20 mL) was added TFA (20 mL) at rt. Thereaction mixture was stirred at rt for 3 h. The reaction mixture wasthen concentration under reduced pressure and the residue was purifiedvia reverse phase column chromatography (ACN/H₂O) to give the titlecompound (1.05 g, 89% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.22 (dd, J=49.8, 8.6 Hz, 1H), 8.00-7.48 (m, 4H), 7.35 (s, 5H),7.23-6.61 (m, 7H), 5.31-4.23 (m, 9H), 4.11-4.03 (m, 2H), 3.75-3.73 (m,2H), 3.62-3.27 (m, 18H), 2.99-2.94 (m, 3H), 2.92-2.80 (m, 2H), 2.79-2.62(m, 3H), 1.96-1.47 (m, 4H), 1.21-1.11 (m, 3H), 0.99 (s, 6H), 0.92 (s,3H). LC/MS (ESI, m/z): [M+1]⁺=918.7.

2-[2-(Tert-butoxycarbonylamino)ethoxy]acetic Acid (Intermediate WF)

Step 1—Ethyl 2-[2-(tert-butoxycarbonylamino)ethoxy]acetate

To a mixture of tert-butyl N-(2-hydroxyethyl)carbamate (10.0 g, 62.0mmol, 9.62 mL, CAS #26690-80-2) and Rh(OAc)₂ (274 mg, 1.24 mmol) in DCM(200 mL) was added a solution of ethyl 2-diazoacetate (10.6 g, 93.0mmol, 9.74 mL, CAS #623-73-4) in DCM (250 mL) dropwise slowly. Thereaction mixture was stirred at 25° C. for 12 hours. On completion, thereaction mixture was diluted with water (200 mL) and extracted with DCM(2×200 mL). The combined organic layers was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (12.0 g, 78% yield) as lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.25 (s, 1H), 4.19 (q, J=7.2 Hz,2H), 4.05 (s, 2H), 3.58 (t, J=5.2 Hz, 2H), 3.31 (q, J=5.2 Hz, 2H), 1.42(s, 9H), 1.26 (t, J=7.1 Hz, 3H).

Step 2—2-[2-(Tert-butoxycarbonylamino)ethoxy]acetic Acid

To a mixture of ethyl 2-[2-(tert-butoxycarbonylamino)ethoxy]acetate(1.00 g, 4.04 mmol) in a mixed solvent of THF (10 mL) and H₂O (5 mL) wasadded LiOH (193 mg, 8.09 mmol). The reaction mixture was stirred at 25°C. for 2 hours. On completion, the reaction mixture was acidified withHCl (1 N) until the pH=5-6, then the mixture was concentrated in vacuoto removed THF, and the residue was extracted with EA (5×10 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated in vacuo to give the title compound (886 mg,99% yield) as light yellow gum. ¹H NMR (400 MHz, DMSO-d₆) δ 7.37 (s,1H), 3.57 (s, 2H), 3.43-3.40 (m, 2H), 3.06 (q, J=5.2 Hz, 2H), 1.37 (s,9H).

3-[5-(aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate WG)

Step 1—5-bromo-N-methyl-2-nitroaniline

To a solution of 4-bromo-2-fluoro-1-nitrobenzene (23 g, 105 mmol) inEtOH (50 mL) was added MeNH₂ (250 ml, 33% in EtOH). After the addition,the mixture was stirred at rt overnight. The reaction mixture wasconcentrated under reduce pressure. The residue was dissolved in EtOAc(300 mL), washed with water (200 mL×2) and brine (200 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to afford the title compound(23 g, 95% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.03 (d,J=9.2 Hz, 2H), 7.01 (s, 1H), 6.76 (d, J=9.2 Hz, 1H), 3.02 (s, 3H). LC/MS(ESI, m/z): [M+1]⁺=231.1

Step 2—5-bromo-N1-methylbenzene-1,2-diamine

To a solution of 5-bromo-N-methyl-2-nitroaniline (23.0 g, 0.10 mol) inAcOH (230 mL)/EtOAc (230 mL)/(50 mL) was added Fe (20 g, 0.36 mol) at50° C. After the addition, the reaction mixture was heated to 80° C. andstirred for 1 h. Then the mixture was cooled to rt and filtered. Thefiltrate was concentrated under reduce pressure. The residue was dilutedwith EtOAc (300 mL) and H₂O (300 mL). The organic layer was washed withH₂O (500 mL×2) and brine (200 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified with column(EA:PE=1:2) to afford the title compound (14 g, 70% yield) as a yellowsolid. LC/MS (ESI, m/z): [M+1]⁺=201.1.

Step 3—6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of 5-bromo-N1-methylbenzene-1,2-diamine (14 g, 69.3 mmol)in THF (200 mL) was added CDI (13.4 g, 83.2 mmol). The reaction mixturewas heated for reflux 2 h under N₂ atmosphere. The reaction mixture wascooled to rt and concentrated under reduce pressure. The residue waspurified with column (EA:PE=1:2) to afford the title compound (10 g, 63%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.0 (s, 1H), 7.33(s, 1H), 7.13 (t, J=8.0 Hz 1H), 6.92 (d, J=8.0 Hz, 1H), 3.26 (s, 3H).LC/MS (ESI, m/z): [M+1]⁺=227.1.

Step4—3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 6-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one(5.0 g, 22.1 mmol) in THF (50 mL) was added t-BuOK (2.48 g, 22.1 mmol)at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then3-bromo-1-(4-methoxybenzyl)piperidine-2,6-dione (6.9 g, 22.1 mmol) wasadded. After addition, the reaction mixture was stirred at r.tovernight. The reaction mixture was diluted with sat.aq. Ammoniachloride, extracted with EA (80 mL×2). The combined organic lays werewashed with H₂O (80 mL×2) and brine (80 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified with column (EtOAc:DCM=1:1) to afford3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(3.7 g, 36.6% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.47(d, J=1.9 Hz, 1H), 7.23-7.13 (m, 3H), 7.00 (d, J=8.4 Hz, 1H), 6.88-6.81(m, 2H), 5.53 (dd, J=13.0, 5.4 Hz, 1H), 4.78 (q, J=14.3 Hz, 2H), 3.72(s, 3H), 3.33 (s, 3H), 3.12-2.95 (m, 1H), 2.86-2.63 (m, 2H), 2.12-2.01(m, 1H). LC/MS (ESI, m/z): [M+1]⁺=458.1.

Step5—3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(7.6 g, 16.6 mmol) in toluene (50 mL) was added methanesulfonic acid (20mL). The reaction solution was heated to 110° C. and stirred for 3 h.The reaction mixture was cooled to rt and concentrated to removetoluene. The residue was diluted with CH₃CN and purified via reversephase column chromatography (CH₃CN/H₂O=5%-80%) to give the titlecompound (3.4 g, 61% yield) as a white solid. ¹H NMR (400 MHz, DMSO) δ11.11 (s, 1H), 7.47 (d, J=1.9 Hz, 1H), 7.21 (dd, J=8.4, 1.9 Hz, 1H),7.10 (d, J=8.4 Hz, 1H), 5.38 (dd, J=12.8, 5.4 Hz, 1H), 3.34 (s, 3H),2.93-2.83 (m, 1H), 2.74-2.60 (m, 2H), 2.03-1.97 (m, 1H). LC/MS (ESI,m/z): [M+1]³⁰=338.1.

Step6—1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

A mixture of3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(5 g, 14.8 mmol), zinc cyanide (6.9 g, 59.2 mmol),tris(dibenzylideneacetone)dipalladium (1.4 g, 1.5 mmol) and1,1′-Ferrocenebis(diphenylphosphine) (1.6 g, 3.0 mmol) in DMF (100 mL)was heated to 120° C. and stirred for 19 h under nitrogen atmosphere insealed tube. The reaction mixture was cooled to rt, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (EA/DCM=2/1) to give the title compound (3 g,71%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.16 (s, 1H), 7.75(d, J=1.5 Hz, 1H), 7.55 (dd, J=8.2, 1.5 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H),5.46 (dd, J=12.8, 5.4 Hz, 1H), 3.38 (s, 3H), 2.83-2.94 (m, 1H),2.59-2.78 (m, 2H), 2.01-2.09 (m, 1H). LC/MS (ESI, m/z): [M+1]⁺=284.9.

Step7—3-(5-(aminomethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dioneacetate

To a solution of1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile(2.3 g, 8.1 mmol) in AcOH (20 mL) was added PtO₂ (98.8 mg, 0.41 mmol)and 10 wt % palladium on activated carbon (850 mg, 0.81 mmol). Themixture was hydrogenated for 1 h at 85 psi at rt. The reaction mixturewas filtered, the filtrate was concentrated under reduced pressure anddried to give the title compound (2.8 g, quant. yield) as a salt withAcOH. ¹H NMR (400 MHz, DMSO-d₆) δ 7.24 (s, 1H), 7.01-7.10 (m, 2H), 5.36(dd, J=12.76, 5.38 Hz, 1H), 3.84 (s, 2H), 3.33 (s, 3H), 2.83-2.96 (m,1H), 2.57-2.78 (m, 2H), 1.97-2.05 (m, 1H), 1.85 (br. s., 6H). LC/MS(ESI, m/z): [M−NH₂]+=272.17.

2-(2-Aminoethoxy)-N-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]acetamide(Intermediate WH)

Step 1—Tert-ButylN-[2-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]-2-oxo-ethoxy]ethyl]carbamate

To a mixture of 2-[2-(tert-butoxycarbonylamino)ethoxy]acetic acid (405mg, 1.85 mmol, Intermediate WF) and DIPEA (994 mg, 7.70 mmol, 1.34 mL)in DMF (5 mL) was added HATU (702 mg, 1.85 mmol). The reaction mixturewas stirred at 0° C. Then,3-[5-(aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (0.50 g, 1.54 mmol, HCl, Intermediate WG) wasadded. The reaction mixture was stirred at 25° C. for 0.5 hour. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% FA condition) to give the title compound(500 mg, 66% yield) as white solid. LC-MS (ESI⁺) m/z 390.2 (M+H−100)⁺.

Step2—2-(2-Aminoethoxy)-N-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]acetamide

To a mixture of tert-butylN-[2-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]-2-oxo-ethoxy]ethyl]carbamate (400 mg, 817 umol) in DCM (5mL) was added HCl/dioxane (4 M, 20 mL). The reaction mixture was stirredat 25° C. for 1 hour. On completion, the reaction mixture wasconcentrated in vacuo. The residue was purified by prep-HPLC (0.1% FAcondition) to give the title compound (240 mg, 75% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 8.53 (t, J=6.0 Hz,1H), 8.03 (s, 2H), 7.12 (s, 1H), 7.08-6.95 (m, 2H), 5.36 (dd, J=5.2,12.8 Hz, 1H), 4.36 (d, J=6.0 Hz, 2H), 3.98 (s, 2H), 3.65 (t, J=5.2 Hz,2H), 3.37 (s, 3H), 3.02 (d, J=4.4 Hz, 2H), 2.97-2.85 (m, 1H), 2.77-2.59(m, 2H), 2.07-1.92 (m, 1H); LC-MS (ESI⁺) m/z 390.2 (M+H)⁺.

3-[4-[4-(4-Aminobutoxy)butyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate WI)

Step 1—Tert-ButylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynoxy]butyl]carbamate

A mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP), tert-butylN-(4-but-3-ynoxybutyl)carbamate (1.07 g, 4.44 mmol, Intermediate SY),CuI (84 mg, 443 umol), Pd(PPh₃)₂Cl₂ (311 mg, 443 umol) and TEA (2.69 g,26.6 mmol) in DMF (10 mL) was degassed and purged with N₂ three times,and then the mixture was stirred at 85° C. for 4 hrs under N₂atmosphere. On completion, the mixture was dilute with H₂O (20 mL), thenextracted with EA (2×60 mL). The organic layer was washed with brine (30mL), dried over anhydrous Na₂SO₄, and then concentrated in vacuo. Theresidue was purified by reversed phase flash to give the title compound(460 mg, 58% yield) as light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.12 (s, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.09-7.04 (m, 1H), 7.02-6.97 (m,1H), 6.79 (s, 1H), 5.39 (dd, J=5.2, 12.8 Hz, 1H), 3.65 (s, 3H), 3.58 (t,J=6.4 Hz, 2H), 3.43 (t, J=6.0 Hz, 2H), 2.96-2.86 (m, 3H), 2.77-2.58 (m,4H), 2.06-1.99 (m, 1H), 1.51-1.40 (m, 4H), 1.37 (s, 9H); LC-MS (ESI⁺)m/z 499.3 (M+1)⁺.

Step 2—Tert-ButylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]butoxy]butyl]carbamate

To a solution of tert-butylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynoxy]butyl]carbamate(460 mg, 922 umol) in THF (50 mL) was added Pd/C (100 mg, 10 wt %) andPd(OH)₂/C (100 mg, 10 wt %). The mixture was stirred at 25° C. for 4 hrsunder H₂ (15 psi). On completion, the mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (463 mg,99% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),6.99-6.95 (m, 2H), 6.89-6.87 (m, 1H), 6.80-6.75 (m, 1H), 5.37 (dd,J=5.2, 12.4 Hz, 1H), 3.55 (s, 3H), 3.40 (t, J=5.6 Hz, 2H), 3.36-3.33 (m,2H), 2.96-2.85 (m, 5H), 2.77-2.58 (m, 2H), 2.05-1.96 (m, 1H), 1.69-1.57(m, 4H), 1.52-1.40 (m, 4H), 1.37 (s, 9H).

Step3—3-[4-[4-(4-Aminobutoxy)butyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]butoxy]butyl]carbamate (460 mg, 915 umol) in DCM (20 mL) was addedHCl/dioxane (4 M, 10 mL). The mixture was stirred at 25° C. for 3 hrs.On completion, the mixture was concentrated in vacuo to give the titlecompound (360 mg, 90% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.01 (s, 1), 7.68 (s, 2H), 6.94-6.85 (m, 2H), 6.81-6.79 (m,1), 5.30 (dd, J=5.2, 12.8 Hz, 1H), 3.49 (s, 3H), 3.37-3.35 (m, 2H),3.31-3.28 (m, 2H), 2.89-2.77 (m, 3H), 2.76-2.55 (m, 4H), 1.97-1.88 (m,1H), 1.61-1.45 (m, 8H); LC-MS (ESI⁺) m/z 403.1 (M+1)⁺.

Tert-ButylN-[4-[4-[[3-(5-formyl-3-pyridyl)-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(Intermediate WJ)

Step 1—Isopropoxycarbonyl5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazol-3-yl]pyridine-3-carboxylate

To a solution of5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazol-3-yl]pyridine-3-carboxylicacid (640 mg, 1.09 mmol, Intermediate WD) and TEA (560 mg, 5.53 mmol) inTHF (20 mL) was added isopropyl carbonochloridate (340 mg, 2.77 mmol) at0° C. Then, the mixture was stirred at 0-10° C. for 2 hours. Oncompletion, the mixture was filtered and the filter cake was washed withTHF (10 mL). The filtrate and washing were combined and used directly inthe next step. LC-MS (ESI⁺) m/z 674.3 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-[5-(hydroxymethyl)-3-pyridyl]-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of isopropoxycarbonyl5-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-1-methyl-pyrazol-3-yl]pyridine-3-carboxylatein THF (30 mL) was added LiBH₄ (147 mg, 6.75 mmol) at 0° C. Then, themixture was stirred at 0-10° C. for 1 hour. On completion, the mixturewas added water (100 mL). The mixture was extracted with EA (3×60 mL).The combined organic layer was concentrated in vacuo. The residue waspurified by reversed phase flash (0.1% FA condition) to give the titlecompound (380 mg, 60% yield via two steps) as light yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 8.94-8.92 (m, 2H), 8.59 (m, 1H), 8.51 (d, J=5.2 Hz,1H), 8.41-8.39 (m, 2H), 8.24 (s, 1), 8.14 (s, 1), 7.68-7.66 (m, 1), 4.89(q, J=8.8 Hz, 2H), 4.81 (s, 2H), 4.01 (s, 3H), 1.59 (s, 9H).

Step 3—Tert-ButylN-[4-[4-[[3-(5-formyl-3-pyridyl)-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-[5-(hydroxymethyl)-3-pyridyl]-1-methyl-pyrazol-4-yl]carbamoyl] oxazol-2-yl]-2-pyridyl]-N-(2, 2, 2-trifluoroethyl) carbamate(360 mg, 573 umol) in DCM (20 mL) was added Dess-Martin (360 mg, 848umol) at 0° C. Then, the mixture was stirred at 3 hours at 0-10° C. Oncompletion, the mixture was diluted with DCM (20 mL), washed with sat.aq. Na₂S₂O₃ (10 mL). The organic layer was washed with sat.NaHCO₃ (10mL) and brine (10 mL), dried over Na₂SO₄, filtered and concentrated invacuo to give the title compound (320 mg, 97% yield) as light yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 10.21 (s, 1), 9.26 (d, J=2.0 Hz, 1),9.08 (d, J=2.0 Hz, 1), 8.82 (s, 1), 8.54-8.52 (m, 2H), 8.41 (s, 1), 8.38(s, 1), 8.18 (s, 1), 7.73 (d, J=1.6 Hz, 1), 4.87 (q, J=8.8 Hz, 2H), 4.01(s, 3H), 1.56 (s, 9H).

2-[2-(Methylamino)ethoxy]ethanol (Intermediate WK)

To a solution of tert-butylN-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (3.00 g, 13.7 mmol,synthesized via Steps 1-2 of Intermediate FY) in DCM (20 mL) was addedHCl/dioxane (4 M, 20 mL). The reaction mixture was stirred at 25° C. for1 hr. On completion, the mixture was concentrated in vacuo to give thetitle compound (2.10 g, 99% yield, HCl salt) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 3.67 (t, J=5.2 Hz, 2H), 3.57-3.51 (m, 2H),3.50-3.46 (m, 2H), 3.13-3.02 (m, 2H), 2.55 (t, J=5.2 Hz, 3H).

Tert-Butyl 4-(2-prop-2-vnoxyethoxy)piperidine-1-carboxylate(Intermediate WM)

Step 1—Tert-Butyl 4-(2-ethoxy-2-oxo-ethoxy)piperidine-1-carboxylate

To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (5.00 g,24.8 mmol, CAS #109384-19-2) and diacetoxyrhodium (274 mg, 1.24 mmol) inDCM (80 mL) was added a solution of ethyl 2-diazoacetate (8.50 g, 74.5mmol) in DCM (60 mL) at 0-10° C. during 2 hours. The mixture was stirredat 25° C. for 40 hours. On completion, the mixture was concentrated invacuo. The residue was purified by column chromatography to give thetitle compound (7.00 g, 98% yield) as light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 4.28-4.20 (m, 2H), 4.12 (s, 2H), 3.81-3.75 (m, 2H), 3.57 (m,1H) 3.12-3.05 (m, 2H), 1.87-1.86 (m, 2H), 1.59-1.52 (m, 2H), 1.46 (s,9H), 1.33-1.28 (s, 3H).

Step 2—Tert-Butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate

To a suspension of LAH (1.59 g, 41.8 mmol) in THF (40 mL) was added asolution of tert-butyl 4-(2-ethoxy-2-oxo-ethoxy)piperidine-1-carboxylate(6.00 g, 16.5 mmol) in THF (20 mL) slowly at 0-10° C. The mixture wasstirred at 0-10° C. for 3 hours. On completion, the reaction wasquenched with water (1.60 mL) slowly at 0-10° C. Then 10% aq.NaOH (1.60mL) and water (4.80 mL) were added to the mixture. The mixture wasfiltered and the filter cake was washed with EA (50 mL). The filtrateand washing were combined and concentrated in vacuo. The residue waspurified by column chromatography on silica gel to give the titlecompound (4.00 g, 67% yield) as light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 3.76-3.75 (m, 2H), 3.74-3.73 (m, 2H), 3.60-3.58 (m, 2H), 3.50(m, 1H), 3.13-3.07 (m, 2H), 1.85-1.84 (m, 2H), 1.57-1.52 (m, 2H), 1.47(s, 9H).

Step 3—Tert-Butyl 4-(2-prop-2-ynoxyethoxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-(2-hydroxyethoxy)piperidine-1-carboxylate(3.80 g, 15.4 mmol) in THF (40 mL) was added NaH (1.86 g, 46.5 mmol, 60%oil dispersion) at 0° C. The mixture was stirred at 25° C. for 0.5 hour.Then 3-bromoprop-1-yne (2.76 g, 23.2 mmol) was added to the mixture at25C. The mixture was stirred at 25° C. for 16 hours. On completion, thereaction was quenched with sat.aq.NH₄Cl (20 mL). The mixture was dilutedwith water (100 mL), then extracted with EA (3×80 mL). The combinedorganic layer was washed with brine (30 mL), dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by columnchromatography to give the title compound (3.70 g, 84% yield) as lightyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.22 (d, J=2.4 Hz, 2H), 3.86-3.75(m, 2H), 3.73-3.62 (m, 4H), 3.53-3.45 (m, 1H), 3.10-3.00 (m, 2H), 2.44(t, J=2.4 Hz, 1H), 1.90-1.80 (m, 2H), 1.56-1.48 (m, 2H), 1.46 (s, 9H).

3-[3-Methyl-2-oxo-5-[3-[2-(4-piperidyloxy)ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate WN)

Step 1—Tert-Butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]piperidine-1-carboxylate

A mixture of tert-butyl 4-(2-prop-2-ynoxyethoxy)piperidine-1-carboxylate(800 mg, 2.82 mmol, Intermediate WM),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HN), CuI (45.0 mg, 236 umol), Pd(PPh₃)₂Cl₂(166 mg, 236 umol), Cs₂CO₃ (1.93 g, 5.91 mmol) and 4Å MS (400 mg) in DMF(15 mL) was stirred at 80° C. for 2 hours. On completion, the reactionmixture was cooled to 20° C. The mixture was diluted with EA (50 mL),filtered and the cake was washed with EA (30 mL). The filtrate andwashing were combined and concentrated in vacuo. The residue waspurified by reversed phase flash (FA condition) to give the titlecompound (420 mg, 65% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.13 (m, 1H), 7.33 (s, 1H), 7.19-7.08 (m, 2H), 5.41-5.37 (m,1H), 4.40 (s, 2H), 4.18-4.11 (m, 1H), 3.63-3.59 (m, 4H), 3.56-3.51 (m,2H), 3.50-3.41 (m, 2H), 3.36 (s, 3H), 2.93-2.83 (m, 1H), 2.76-2.61 (m,2H), 2.07-1.99 (m, 1H), 1.80-1.75 (m, 2H) 1.38 (s, 9H), 1.35-1.30 (m,2H).

Step 2—Tert-Butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]piperidine-1-carboxylate

A mixture of tert-butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]piperidine-1-carboxylate (400 mg, 739 umol),Pd(OH)₂/C (100 mg, 739 umol, 10 wt %) and Pd/C (100 mg, 739 umol, 10 wt%) in THF (20 mL) was stirred at 25° C. for 20 hours under H₂ (15 psi).On completion, the mixture was filtered, and the cake was washed with EA(10 mL). The filtrate and washing were combined and concentrated invacuo to give the title compound (400 mg, 99% yield) as light yellowgum. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 6.94-6.89 (m, 1H), 6.88 (s,1H), 6.72 (d, J=8.0 Hz, 1H), 5.25-5.18 (m, 1H), 3.75-3.70 (m, 1H),3.60-3.56 (m, 2H), 3.52-3.46 (m, 4H), 3.43 (s, 3H), 3.11-3.02 (m, 3H),2.90-2.83 (m, 1H), 2.77-2.70 (m, 3H), 2.27-2.21 (m, 1H), 1.93-1.91 (m,2H), 1.88-1.81 (m, 3H), 1.64-1.60 (m, 1H), 1.55-1.51 (m, 2H), 1.46 (s,9H).

Step3—3-[3-Methyl-2-oxo-5-[3-[2-(4-piperidyloxy)ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]piperidine-1-carboxylate (100 mg, 183 umol) in DCM (3.0mL) was added TFA (1.0 mL) at 20° C. The reaction mixture was stirred at20° C. for 1 hour. On completion, the mixture was concentrated in vacuoto give the title compound (81.0 mg, 99% yield) as light yellow gum.LC-MS (ESI⁺) m/z 445.3 (M+H)⁺.

Tert-ButylN-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate(Intermediate WP)

Step 1—Benzyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate

To a solution of [(2R)-morpholin-2-yl]methanol (2.50 g, 16.2 mmol, HCl,CAS #156925-22-3), NaHCO₃ (4.10 g, 48.8 mmol) in a mixed solvent of ACN(80.0 mL) and H₂O (80.0 mL) was added CbzCl (4.16 g, 24.4 mmol, 3.47 mL)at 0° C. dropwise. The mixture was then stirred at 25° C. for 16 hrs. Oncompletion, the mixture was concentrated in vacuo to remove ACN. Thenthe mixture was extracted with EA (2×20 mL), and the combined organiclayers were concentrated in vacuo. The residue was purified by silicagel column (PE:EA=1:1) to give the title compound (3.7 g, 90% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.33 (m, 5H), 5.17 (d,J=2.0 Hz, 2H), 4.08-3.88 (m, 3H), 3.77-3.65 (m, 1H), 3.63-3.46 (m, 3H),3.13-2.73 (m, 2H), 2.07-1.96 (m, 1H).

Step 2—Benzyl (2R)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate

To a solution of benzyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate(3.70 g, 14.7 mmol), and TEA (4.47 g, 44.1 mmol) in DCM (40.0 mL) wasadded MsCl (2.53 g, 22.0 mmol) at 0° C., then the mixture was stirred at25° C. for 1 hr. On completion, the mixture was diluted with DCM (20 mL)and washed with H₂O (3×30 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (4.85 g, 100% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.43-7.33 (m, 5H), 5.20-5.15 (m, 2H), 4.26 (d, J=4.8 Hz, 2H), 4.10-3.83(m, 3H), 3.80-3.65 (m, 1H), 3.63-3.48 (m, 1H), 3.08 (s, 3H), 3.07-2.75(m, 2H).

Step 3—Benzyl (2S)-2-(methylaminomethyl)morpholine-4-carboxylate

To a solution of benzyl(2R)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (4.3 g, 13.0mmol) in EtOH (10.0 mL) was added MeNH₂ (40.5 g, 391 mmol, 30% solutionin ethanol), and the mixture was stirred at 80° C. for 16 hrs in a 100mL of autoclave. On completion, the mixture was concentrated in vacuo togive the title compound (3.45 g, 100% yield) as yellow oil. LC-MS (ESI⁺)m/z 265.1 (M+H)⁺.

Step 4—Benzyl(2S)-2-[[tert-butoxycarbonyl(methyl)amino]methyl]morpholine-4-carboxylate

To a solution of benzyl(2S)-2-(methylaminomethyl)morpholine-4-carboxylate (3.45 g, 13.0 mmol)in MeOH (50.0 mL) was added TEA (1.58 g, 15.6 mmol, 2.18 mL). Then(Boc)₂O (4.27 g, 19.5 mmol, 4.50 mL) was added into the above mixturedropwise. The mixture was stirred at 25° C. for 2 hrs. On completion,the mixture was concentrated in vacuo. The residue was purified bysilica gel column (PE:EA=5:1) to give the title compound (4.10 g, 86%yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.30 (m, 5H),5.24-5.09 (m, 2H), 4.11-3.83 (m, 3H), 3.68-3.34 (m, 3H), 3.30-3.14 (m,1H), 3.09-2.97 (m, 1H), 2.94 (s, 3H), 2.80-2.62 (m, 1H), 1.47 (s, 9H).

Step 5—Tert-Butyl N-methyl-N-[[(2R)-morpholin-2-yl]methyl]carbamate

To a solution of benzyl(2S)-2-[[tert-butoxycarbonyl(methyl)amino]methyl]morpholine-4-carboxylate(4.10 g, 11.2 mmol) in MeOH (40.0 mL) was added Pd/C (1.00 g, 10% wt),and the mixture was stirred at 25° C. for 16 hrs under H₂ (15 psi). Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo to give the title compound (2.54 g, 98% yield) as colorlessoil. ¹H NMR (400 MHz, DMSO-d₆) δ 3.75-3.65 (m, 1H), 3.50-3.42 (m, 1H),3.41-3.37 (m, 1H), 3.24-3.13 (m, 1H), 3.10-3.03 (m, 1H), 2.85-2.75 (m,3H), 2.70-2.53 (m, 4H), 2.37-2.23 (m, 1H), 1.39 (s, 9H).

Step 6—Tert-ButylN-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate

To a solution of tert-butylN-methyl-N-[[(2R)-morpholin-2-yl]methyl]carbamate (1.00 g, 4.34 mmol),3-bromoprop-1-yne (516 mg, 4.34 mmol, CAS #106-96-7) in DMF (10.0 mL)was added K₂CO₃ (3.00 g, 21.7 mmol). The mixture was stirred at 25° C.for 2 hrs. On completion, the mixture was diluted with H₂O (20 mL), thenextracted with EA (2×20 mL). The combined organic layers were washedwith brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated in vacuo. The residue was purified by silicagel column (PE:EA=5:1) to give the title compound (960 mg, 82% yield) asyellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 3.85-3.76 (m, 1H), 3.63-3.52 (m,1H), 3.50-3.40 (m, 1H), 3.30-3.24 (m, 2H), 3.20-3.14 (m, 2H), 2.84-2.78(m, 3H), 2.68-2.55 (m, 2H), 2.54-2.52 (m, 1H), 2.30-2.16 (m, 1H),2.03-1.90 (m, 1H), 1.39 (s, 9H).

3-[3-Methyl-5-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate WO)

Step 1—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]]-Nmethyl-carbamate

To a solution of tert-butylN-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (571 mg,2.13 mmol, Intermediate WP),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HN) in DMF (15.0 mL) was added Pd(PPh₃)₂Cl₂(83.0 mg, 118 umol), 4Å molecular sieves (50.0 mg), Cs₂CO₃ (1.93 g, 5.91mmol) and CuI (22.5 mg, 118 umol). The mixture was stirred at 80° C. for2 hrs under N₂. On completion, the mixture was filtered and the filtratewas concentrated in vacuo. The residue was purified by reverse phase(0.1% FA) to give the title compound (400 mg, 64% yield) as yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.17 (d, J=8.0 Hz, 1),7.10 (s, 1), 6.74 (d, J=8.0 Hz, 1), 5.25-5.14 (m, 1H), 3.99-3.90 (m,1H), 3.82-3.65 (m, 2H), 3.57-3.47 (m, 2H), 3.43 (s, 3H), 3.25-3.14 (m,1H), 3.00-2.94 (m, 1H), 2.94 (s, 3H), 2.89-2.82 (m, 2H), 2.82-2.74 (m,2H), 2.74-2.63 (m, 1H), 2.50-2.38 (m, 1H), 2.30-2.21 (m, 1H), 2.20-2.13(m, 1H), 1.45 (s, 9H).

Step2—3-[3-Methyl-5-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyl]morpholin-2-yl]methyl]-N-methyl-carbamate (150 mg, 285 umol)in DCM (5.00 mL) was added TFA (7.70 g, 67.5 mmol, 5.00 mL). The mixturewas stirred at 20° C. for 1 hr. On completion, the mixture wasconcentrated in vacuo to give the title compound (150 mg, 97% yield, TFAsalt) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 8.83(s, 1H), 7.37 (d, J=1.2 Hz, 1H), 7.27-7.22 (m, 1), 7.22-7.17 (m, 1),5.47-5.37 (m, 1), 4.39-4.21 (m, 3H), 4.18-4.14 (m, 1H), 4.09-4.03 (m,1H), 3.84-3.73 (m, 1H), 3.58-3.44 (m, 2H), 3.36 (s, 3H), 3.27-3.17 (m,1H), 3.12-3.02 (m, 2H), 2.95-2.84 (m, 2H), 2.68-2.62 (m, 1H), 2.60-2.57(m, 3H), 2.09-2.00 (m, 1H).

3-[3-methyl-4-[4-[4-(methylamino)butoxy]butyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate WR)

Step 1 Tert-ButylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynoxy]butyl]-N-methyl-carbamate

To a solution of tert-butyl N-(4-but-3-ynoxybutyl)-N-methyl-carbamate(500 mg, 1.96 mmol, Intermediate RS) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (221mg, 653 umol, Intermediate HP) in DMF (10 mL) was added CuI (24.8 mg,131 umol), Cs₂CO₃ (213 mg, 653 umol), Pd(PPh₃)₂Cl₂ (91.6 mg, 131 umol)and 4Å molecular sieves (200 mg, 653 umol) at 25° C. The reactionmixture was stirred at 80° C. for 2 hours. On completion, the reactionmixture was filtered and concentrated in vacuo. The residue was dilutedwith water (30 mL), and then extracted with EA (3×50 mL). The combinedorganic layers were washed with brine (30 mL), dried over Na₂SO₄,filtered and the filtrate was concentrated in vacuo. The residue waspurified by reverse phase (FA condition) to give the title compound (320mg, 95% yield) as a purple solid. LC-MS (ESI⁺) m/z 413.2 (M+H−100)⁺.

Step 2—Tert-ButylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]butoxy]butyl]-N-methyl-carbamate

To a solution of tert-butylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynoxy]butyl]-N-methyl-carbamate (300 mg, 585 umol) in THF (20 mL)was added Pd(OH)₂/C (500 mg, 585 umol, 20 wt %) and Pd/C (500 mg, 585umol, 10 wt %) at 25° C. The reaction mixture was stirred at 25° C. for2 hours under H₂ (15 psi). On completion, the reaction mixture wasfiltered through celite and the filtrate was concentrated in vacuo togive the title compound (280 mg, 92% yield) as colorless oil. LC-MS(ESI⁺) m/z 417.3 (M+H−100)⁺.

Step3—3-[3-methyl-4-[4-[4-(methylamino)butoxy]butyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]butoxy]butyl]-N-methyl-carbamate (140 mg, 271 umol) in DCM (10 mL) wasadded TFA (5 mL) at 25° C. The reaction mixture was stirred at 25° C.for 2 hours. On completion, the reaction mixture was concentrated invacuo to give the title compound (110 mg, 97% yield) as colorless oil.LC-MS (ESI⁺) m/z 417.2 (M+H)⁺.

Tert-Butyl (3R)-3-prop-2-ynoxypyrrolidine-1-carboxylate (IntermediateWU)

To a mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (5.00g, 26.7 mmol, CAS #109431-87-0) and TBAI (493 mg, 1.34 mmol) in THF (50mL) was added sodium hydride (1.28 g, 32.0 mmol, 60% oil dispersion) inportions at 0° C. After 0.5 hour, 3-bromoprop-1-yne (6.35 g, 53.4 mmol)was added to the mixture. The reaction mixture was stirred at 0-25° C.for 12.5 hours. On completion, the reaction was quenched with water (1.0mL). The mixture was filtrated and the filtrate was concentrated invacuo. The residue was purified by silica gel chromatography on silicagel to give the title compound (6.00 g, 99% yield) as yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 4.28 (s, 1H), 4.24-4.06 (m, 2H), 3.55-3.32 (m, 4H),2.44 (t, J=2.4 Hz, 1H), 2.13-1.88 (m, 2H), 1.46 (s, 9H).

3-[3-Methyl-2-oxo-4-[3-[(3R)-pyrrolidin-3-yl]oxypropyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate WV)

Step 1—Tert-Butyl(3R)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]pyrrolidine-1-carboxylate

A mixture of tert-butyl (3R)-3-prop-2-ynoxypyrrolidine-1-carboxylate(666 mg, 2.96 mmol, Intermediate WU),3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HP), Pd(PPh₃)₂Cl₂ (166 mg, 236 umol), CuI(45.0 mg, 236 umol), 4Å MS (100 mg, 1.18 mmol) and Cs₂CO₃ (1.93 g, 5.91mmol) in DMF (8 mL) was stirred at 80° C. for 2 hours under N₂. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by reverse phase (FAcondition) to give the title compound (330 mg, 57% yield) as brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.18 (d, J=7.6 Hz,1H), 7.13 (d, J=7.6 Hz, 1H), 7.06-7.00 (m, 1H), 5.42-5.38 (m, 1H), 4.48(s, 2H), 4.34-4.24 (m, 1H), 3.63 (s, 3H), 3.37-3.35 (m, 1H), 3.27-3.17(m, 2H), 2.95-2.82 (m, 1H), 2.77-2.63 (m, 2H), 2.07-1.89 (m, 4H), 1.38(d, J=9.6 Hz, 9H).

Step 2—Tert-Butyl(3R)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]pyrrolidine-1-carboxylate

To a solution of tert-butyl(3R)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]pyrrolidine-1-carboxylate (300 mg, 621 umol) in THF (10 mL)was added Pd/C (150 mg, 10 wt %) and Pd(OH)₂/C (150 mg, 20 wt %) at 20°C. The reaction mixture was stirred at 20° C. for 12 hours under H₂ (15psi). On completion, the reaction mixture was filtered and the filtratewas concentrated in vacuo to give the title compound (300 mg, 99% yield)as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 6.99-6.92 (m,2H), 6.90-6.82 (m, 1H), 5.42-5.38 (m, 1H), 4.06-3.96 (m, 1H), 3.55 (s,3H), 3.50-3.39 (m, 2H), 3.32-3.30 (m, 1H), 3.30-3.26 (m, 2H), 3.26-3.20(m, 1H), 2.98-2.91 (m, 2H), 2.90-2.82 (m, 1H), 2.75-2.57 (m, 2H),2.03-1.95 (m, 1H), 1.94-1.86 (m, 2H), 1.85-1.74 (m, 2H), 1.40 (s, 9H).

Step3—3-[3-Methyl-2-oxo-4-[3-[(3R)-pyrrolidin-3-yl]oxypropyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl (3R)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl] propoxy]pyrrolidine-1-carboxylate (300 mg, 616 umol) in dichloromethane (3 mL)was added TFA (3 mL) at 15° C. The reaction mixture was stirred at 15°C. for 0.5 hour. On completion, the reaction mixture was concentrated invacuo to give the title compound (330 mg, 100% yield, TFA salt) asyellow semisolid. LC-MS (ESI⁺) m/z 387.2 (M+H)⁺.

1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(Intermediate WW)

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP) in DMF (20 mL) was added TEA (448 mg,4.44 mmol), Pd(dppf)Cl₂ (162 mg, 221 umol) and Et₃SiH (515 mg, 4.44mmol). The reaction mixture was stirred at 80° C. for 16 hours under CO(50 Psi). On completion, the reaction mixture was concentrated in vacuoand purified by reverse phase (0.1% FA) to give the title compound (400mg, 47% yield) as a white solid. LC-MS (ESI⁺) m/z 288.0 (M+H)⁺.

3-[3-Methyl-4-[[4-(methylamino)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate WX)

Step 1—Tert-ButylN-[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]-N-methyl-carbamate

To a solution of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(160 mg, 556 umol, Intermediate WW) and tert-butylN-methyl-N-(4-piperidyl)carbamate (119 mg, 556 umol) in a mixed solventsof THF (3 mL) and DMF (1.5 mL) was added AcOH until the pH=5-7. Afterthe reaction mixture was stirred at 20° C. for 3 hours. NaBH(OAc)₃ (177mg, 835 umol) was added to the reaction mixture. The mixture was stirredat 20° C. for 12 hours. On completion, the reaction mixture was quenchedby water (3 drops) and filtered. The filtrate was concentrated in vacuo.The residue was purified by reverse phase (FA condition) to give thetitle compound (220 mg, 46% yield) as white solid. LC-MS (ESI⁺) m/z486.2 (M+H)⁺.

Step2—3-[3-Methyl-4-[[4-(methylamino)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]-N-methyl-carbamate(200 mg, 235 umol) in DCM (3 mL) was added TFA (3 mL). The reactionmixture was stirred at 15° C. for 0.5 hour. On completion, the reactionmixture was concentrated in vacuo to give the title compound (220 mg,100% yield, TFA salt) as yellow oil. LC-MS (ESI⁺) m/z 386.2 (M+H)⁺.

3-[3-Methyl-4-[4-[4-(methylaminomethyl)-1-piperidyl]but-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate WZ)

Step1—3-[4-(4-Hydroxybut-1-ynyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00g, 2.96 mmol, Intermediate HP) and but-3-yn-1-ol (518 mg, 7.39 mmol, 559uL, CAS #927-74-2) in DMSO (15 mL) was added Pd(PPh₃)₂Cl₂ (207 mg, 295umol), CuI (56.3 mg, 295 umol) and DIPEA (1.91 g, 14.7 mmol, 2.58 mL).The reaction mixture was stirred at 80° C. for 2 hrs under N₂. Oncompletion, the mixture was filtered, and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (600 mg, 62% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.15-6.97 (m,3H), 5.39 (dd, J=4.8, 12.4 Hz, 1H), 4.94 (s, 1H), 3.65 (s, 3H), 3.34 (s,2H), 2.95-2.84 (m, 1H), 2.69-2.59 (m, 4H), 2.06-2.00 (m, 1H); LC-MS(ESI⁺) m/z 328.1 (M+H)⁺.

Step2—4-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynylmethane sulfonate

To a solution of3-[4-(4-hydroxybut-1-ynyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(600 mg, 1.83 mmol) and TEA (556 mg, 5.50 mmol, 765 uL) in DCM (20 mL)was added MsCl (314 mg, 2.75 mmol, 212 uL) dropwise at 0° C. Thereaction mixture was stirred at 25° C. for 2 hrs. On completion, thereaction mixture was quenched with H₂O (30 mL), then extracted with DCM(2×50 mL). The organic phase was dried with Na₂SO₄, filtrated andconcentrated in vacuo to give the title compound (500 mg, 67% yield) asa yellow solid. LC-MS (ESI⁺) m/z 406.2 (M+H)⁺.

Step 3—Tert-ButylN-[[1-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynyl]-4-piperidyl]methyl]-N-methyl-carbamate

To a solution of4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynylmethanesulfonate (400 mg, 986 umol) and tert-butylN-methyl-N-(4-piperidylmethyl)carbamate (270 mg, 1.18 mmol, CAS#138022-04-5) in MeCN (10 mL) and CHCl₃ (10 mL) was added K₂CO₃ (409 mg,2.96 mmol). The reaction mixture was stirred at 65° C. for 16 hrs. Oncompletion, the reaction mixture was diluted with water (30 mL) andextracted with EA (3×50 mL). The combined organic layers was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (140 mg, 26% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.11 (s, 1H), 7.11 (d, J=7.2 Hz, 1H), 7.07-7.02 (m, 1H),7.01-6.96 (m, 1H), 5.38 (dd, J=5.2, 12.8 Hz, 1H), 3.67 (s, 3H), 3.05 (d,J=6.4 Hz, 2H), 2.96-2.87 (m, 3H), 2.69-2.58 (m, 9H), 2.05-1.94 (m, 3H),1.58-1.51 (m, 3H), 1.38 (s, 9H), 1.18-1.08 (m, 2H); LC-MS (ESI⁺) m/z538.4 (M+H)⁺.

Step4—3-[3-Methyl-4-[4-[4-(methylaminomethyl)-1-piperidyl]but-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[1-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynyl]-4-piperidyl]methyl]-N-methyl-carbamate (140 mg, 260 umol) inDCM (3 mL) was added ZnBr₂ (293 mg, 1.30 mmol, 65.1 uL). The reactionmixture was stirred at 20° C. for 48 hrs. On completion, the reactionmixture was concentrated in vacuo to give a residue. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(100 mg, 87% yield) as a white solid. LC-MS (ESI⁺) m/z 438.2 (M+H)⁺.

Tert-Butyl (2,2-difluoro-3-(prop-2-yn-1-yloxy)propyl)(methyl)carbamate(Intermediate XA)

Step 1—Tert-Butyl (2,2-difluoro-3-hydroxypropyl)carbamate

To a solution of 3-amino-2,2-difluoro-propan-1-ol (2.00 g, 18.0 mmol,CAS #155310-11-5) in a mixed solvents of THF (75 mL) and H₂O (75 mL) wasadded Boc₂O (3.93 g, 18.0 mmol) slowly at 0° C. The reaction mixture wasstirred at 25° C. for 16 hours. On completion, the reaction mixture wasdiluted with 1.0 M aq.HCl (100 mL) and extracted with EA (2×150 mL). Thecombined organic phase was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (3.76 g,98% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 5.04 (s, 1H),4.10-3.87 (m, 1H), 3.76-3.63 (m, 2H), 3.60-3.54 (m, 2H), 1.48 (s, 9H).

Step 2—Tert-Butyl (2,2-difluoro-3-(prop-2-yn-1-yloxy)propyl)carbamate

To a solution of tert-butyl N-(2,2-difluoro-3-hydroxy-propyl)carbamate(5.00 g, 23.7 mmol) in THF (100 mL) was added KOH (1.33 g, 23.7 mmol),KI (393 mg, 2.37 mmol), TBAI (1.31 g, 3.55 mmol) and 3-bromoprop-1-yne(4.22 g, 28.41 mmol) at 25° C. The reaction mixture was stirred at 25°C. for 16 hours. On completion, the reaction mixture was diluted withsat. aq. NH₄Cl (100 mL) and extracted with EA (2×150 mL). The combinedorganic phase was concentrated in vacuo. The residue was purified bysilica gel chromatography (PE:EA=40:1) to give title compound (3.27 g,55% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.95-4.73 (m,1H), 4.30-4.24 (m, 2H), 3.84-3.74 (m, 2H), 3.72-3.58 (m, 2H), 2.56-2.46(m, 1H), 1.47 (s, 9H).

Step 3—Tert-Butyl(2,2-difluoro-3-(prop-2-yn-1-yloxy)propyl)(methyl)carbamate

To solution of tert-butylN-(2,2-difluoro-3-prop-2-ynoxy-propyl)carbamate (3.00 g, 12.1 mmol) inTHF (50 mL) was added NaH (578 mg, 14.4 mmol, 60% dispersion in mineraloil) at 0° C. The mixture was stirred at 0° C. for 0.5 hour, then MeI(3.42 g, 24.1 mmol) was added. The reaction mixture stirred at 0-25° C.for 2 hours. On completion, the reaction was queched with water (100mL). The mixture was extracted with EA (2×100 mL). The combined organicphase was concentrated in vacuo to give the title compound (3.00 g, 95%yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.25-4.18 (m, 2H),3.72-3.58 (m, 4H), 2.89 (s, 3H), 2.42 (s, 1H), 1.40 (s, 9H).

3-(4-(3-(2,2-Difluoro-3-(methylamino)propoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(Intermediate XB)

Step 1—Tert-Butyl(3-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)-2,2-difluoropropyl)(methyl)carbamate

To a solution of tert-butylN-(2,2-difluoro-3-prop-2-ynoxy-propyl)carbamate (442 mg, 1.77 mmol,Intermediate XA) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300mg, 887 umol, Intermediate HP) in DMF (6 mL) was added Pd(PPh₃)₂Cl₂ (125mg, 177 umol), CuI (33.8 mg, 177 umol), Cs₂CO₃ (1.45 g, 4.44 mmol) and4Å molecular sieves (100 mg) at 20° C. The mixture was stirred at 80° C.for 2 hours under N₂. On completion, the reaction mixture was cooled to20° C. The mixture was diluted with EA (50 mL) and filtered. Thefiltrate was washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by reverse phase (FAcondition) to give the title compound (160 mg, 35% yield) as brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.24-7.17 (m, 1),7.17-7.11 (m, 1), 7.08-7.01 (m, 1), 5.46-5.35 (m, 1), 4.58 (s, 2H),3.89-3.78 (m, 2H), 3.78-3.68 (m, 2H), 3.67-3.59 (m, 3H), 1.38 (s, 9H).LC-MS (ESI⁺) m/z 543.1 (M+Na)⁺.

Step 2—Tert-Butyl(3-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)-2,2-difluoropropyl)(methyl)carbamate

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]-2,2-difluoro-propyl]-N-methyl-carbamate (200 mg, 384 umol)in THF (10 mL) was added Pd/C (50.0 mg, 10 wt %) and Pd(OH)₂/C (50.0 mg,10 wt %) at 25° C. The mixture was stirred at 25° C. for 18 hours underH₂ (15 psi). On completion, the reaction mixture was diluted with THF(40 mL), filtrated and concentrated in vacuo to give the title compound(195 mg, 97% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08(s, 1H), 7.01-6.94 (m, 2H), 6.91-6.84 (m, 1H), 5.40-5.33 (m, 1H),3.64-3.58 (m, 6H), 3.58-3.56 (m, 3H), 3.02-2.93 (m, 2H), 2.87 (s, 3H),1.91-1.82 (m, 2H), 1.79-1.74 (m, 4H), 1.40 (s, 9H); LC-MS (ESI⁺) m/z547.3 (M+Na)⁺.

Step3—3-(4-(3-(2,2-Difluoro-3-(methylamino)propoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To the solution of tert-butyl N-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl] propoxy]-2,2-difluoro-propyl]-N-methyl-carbamate (180 mg, 343 umol) in DCM (3 mL)was added HCl/dioxane (3 mL) at 25° C. The reaction mixture was stirredat 25° C. for 2 hours. On completion, the mixture was concentrated invacuo to give the title compound (155 mg, 98% yield, HCl salt). LC-MS(ESI⁺) m/z 425.1 (M+H)⁺.

3-[6-[3-[3-(Methylamino)propoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione(Intermediate XC)

Step 1—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate

To a mixture of3-(6-bromo-2-oxo-1,3-benzoxazol-3-yl)piperidine-2,6-dione (450 mg, 1.38mmol, Intermediate OZ), tert-butylN-methyl-N-(3-prop-2-ynoxypropyl)carbamate (566 mg, 2.49 mmol,Intermediate PO) in DMF (10 mL) was added Cs₂CO₃ (2.25 g, 6.92 mmol),CuI (79.08 mg, 415.24 umol), Pd(PPh₃)₂Cl₂ (97.1 mg, 138 umol) andmolecular sieves 4A (50 mg). The reaction mixture was stirred at 80° C.for 2 hours under N₂. On completion, the reaction was filtered. And thefiltrate was poured into water (100 mL), then the aqueous phase wasextracted with ethyl acetate (2×40 mL). The combined organic phase waswashed with brine (2×40 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the residue. The residue was purified byreversed-phase HPLC (0.10% FA condition) to give the title compound (350mg, 49% yield) as a brown solid. ¹H NMR (300 MHz, CDCl₃) δ 8.24-8.11 (m,1H), 7.35 (s, 2H), 6.78 (d, J=8.4 Hz, 1H), 5.06 (d, J=5.2, 12.8 Hz, 1H),4.37 (s, 2H), 3.60 (d, J=6.4 Hz, 2H), 3.34 (d, J=6.8 Hz, 2H), 2.89 (s,3H), 1.94-1.78 (m, 3H), 1.75-1.61 (m, 3H), 1.47 (s, 9H).

Step 2—Tert-ButylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]propyl]-N-methyl-carbamate

To a mixture of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate (350 mg, 742 umol) in THF (10 mL) was addedPd/C (50 mg, 10 wt %) and Pd(OH)₂/C (50 mg, 10 wt %) under N₂. Thesuspension was degassed under vacuum and purged with H₂ three times. Themixture was stirred at 25° C. for 12 hours under H₂ (15 psi). Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (330 mg, 93% yield) asbrown oil. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.12 (s, 1H), 7.00(d, J=8.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1), 5.06 (d, J=5.6, 13.2 Hz, 1),3.41 (q, J=6.4 Hz, 4H), 3.30 (s, 2H), 3.03-2.94 (m, 1H), 2.89-2.84 (m,3H), 2.78-2.68 (m, 3H), 2.37-2.26 (m, 1H), 1.94-1.72 (m, 4H), 1.63 (d,J=6.8 Hz, 2H), 1.46 (s, 8H).

Step3—3-[6-[3-[3-(Methylamino)propoxy]propyl]-2-oxo-1,3-benzoxazol-3-yl]piperidine-2,6-dione

To a mixture of tert-butylN-[3-[3-[3-(2,6-dioxo-3-piperidyl)-2-oxo-1,3-benzoxazol-6-yl]propoxy]propyl]-N-methyl-carbamate (320 mg, 673 umol) in DCM (10 mL) was addedTFA (153 mg, 1.35 mmol). The reaction mixture was stirred at 25° C. for1 hour. On completion, the reaction mixture was concentrated in vacuo togive the title compound (320 mg, 97% yield, TFA salt) as a white solid.LC-MS (ESI⁺) m/z 376.2 (M+H)⁺.

3-[3-Methyl-4-[3-[3-(methylamino)propoxy]prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate XD)

To a mixture of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate(180 mg, 371 umol, synthesized via Step 1 of Intermediate PP) in DCM (5mL) was added TFA (7.70 g, 67.5 mmol, 5.00 mL). The reaction mixture wasstirred at 25° C. for 2 hours. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (180 mg, 97% yield, TFAsalt) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 8.35(s, 2H), 7.19 (d, J=7.6 Hz, 1H), 7.14-7.11 (m, 1H), 7.06-7.01 (m, 1H),5.40 (dd, J=12.8 Hz, 1H), 4.45 (s, 3H), 3.65 (s, 3H), 3.60 (s, 2H), 2.97(m, 2H), 2.91-2.83 (m, 1H), 2.73-2.60 (m, 2H), 2.52-2.50 (m, 2H),2.06-1.99 (m, 1H), 1.90-1.83 (m, 2H).

2-(Methylamino)ethylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]carbamate (Intermediate XE)

Step 1—2-[Tert-butoxycarbonyl(methyl)amino]ethyl (4-nitrophenyl)carbonate

To a mixture of tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (1.00g, 5.71 mmol, CAS #57561-39-4) and (4-nitrophenyl) carbonochloridate(1.15 g, 5.71 mmol, CAS #7693-46-1) in DCM (20 mL) was added TEA (1.44g, 14.27 mmol) at 0° C. for 1 hour. On completion, the reaction waspoured into the ice-water (50 mL) and extracted with DCM (2×30 mL). Thecombined organic phase was washed with brine (2×50 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (1.80 g, 92% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ8.30 (d, J=9.2 Hz, 2H), 7.41 (d, J=9.2 Hz, 2H), 4.41 (t, J=5.6 Hz, 2H),3.61 (s, 2H), 2.98 (s, 3H), 1.48 (s, 9H).

Step2—Tert-butylN-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylcarbamoyloxy]ethyl]-N-methyl-carbamate

To a mixture of 2-[tert-butoxycarbonyl(methyl)amino]ethyl(4-nitrophenyl) carbonate (172 mg, 507 umol),3-[5-(aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(102 mg, 253umol, TFA salt, Intermediate PH) in DMF (10 mL) was addedTEA (128 mg, 1.27 mmol). The reaction mixture was stirred at 25° C. for1 hour. On completion, the reaction mixture was concentrated in vacuo togive the residue. The residue was purified by reversed-phase HPLC (0.1%FA condition) to give the title compound (105 mg, 84% yield) as brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.69 (s, 1H),7.09-7.02 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 5.39-5.32 (m, 1H), 4.21 (d,J=6.0 Hz, 2H), 4.10-4.03 (m, 2H), 3.36 (t, J=5.6 Hz, 2H), 2.97-2.85 (m,1H), 2.80 (s, 2H), 2.74 (d, J=4.4, 8.8 Hz, 1H), 2.67-2.59 (m, 1H),2.10-1.59 (m, 3H), 1.37 (s, 9H).

Step3—2-(Methylamino)ethylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]carbamate

To a mixture of tert-butylN-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylcarbamoyloxy]ethyl]-N-methyl-carbamate (105 mg, 214 umol) in DCM(10 mL) was added TFA (24.4 mg, 214 umol). The reaction mixture wasstirred at 25° C. for 0.5 hour. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (107 mg, 99% yield, TFAsalt) as brown oil. LC-MS (ESI⁺) m/z 390.1 (M+H)⁺.

3-(5-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (IntermediateXF)

Step 1—N-(3-bromophenyl)-3-nitro-pyridin-2-amine

To a solution of 2-chloro-3-nitro-pyridine (5.00 g, 315 mmol, CAS#34515-82-7) and 3-bromoaniline (5.97 g, 34.7 mmol, CAS #591-19-5) indioxane (40 mL) was added DIPEA (12.2 g, 94.6 mmol). The reactionmixture was stirred at 115° C. for 2 days. Then the mixture wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound (8.00 g, 86% yield) as ared solid. LC/MS (ESI, m/z): [M+1]⁺=295.1.

Step 2—N2-(3-bromophenyl)pyridine-2,3-diamine

To a solution of N-(3-bromophenyl)-3-nitro-pyridin-2-amine (5.00 g, 17.0mmol) and NH₄Cl (9.09 g, 170 mmol) in a mixed solvent of H₂O (80 mL) andEtOH (80 mL) was added Fe (9.49 g, 170 mmol). The reaction mixture wasstirred at 80° C. for 1 h. The mixture was then diluted with water (80mL) and extracted with EA (2×80 mL). The organic layers were washed withbrine (2×30 mL), dried with Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure to give the title compound (4.00 g,89% yield) as a brown solid. LC/MS (ESI, m/z): [M+1]⁺=265.1.

Step 3—3-(3-Bromophenyl)triazolo[4,5-b]pyridine

To a solution of N2-(3-bromophenyl)pyridine-2,3-diamine (4.00 g, 15.1mmol) in a mixed solvent of HOAc (25 mL) and DCM (25 mL) was added asolution of NaNO₂ (1.36 g, 19.7 mmol) in H₂O (15 mL) dropwise at 0° C.The reaction mixture was stirred at 25° C. for 30 minutes. Oncompletion, the mixture was diluted with water (50 mL), and extractedwith DCM (2×50 mL). The organic layers were washed with brine (2×50 mL),dried with Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure to give the title compound (4.10 g, 98% yield) as abrown solid. LC/MS (ESI, m/z): [M+1]⁺=276.1.

Step 4—5-Bromo-9H-pyrido[2,3-b]indole

A mixture of 3-(3-bromophenyl)triazolo[4,5-b]pyridine (3.60 g, 13.1mmol) in PPA (20 mL) was heated at 170° C. for 3 h. On completion, themixture was poured into the ice water (200 mL), stirred for 1 h, thenfiltered. The filter cake was dried under reduced pressure. The filtercake contained two isomers 5-bromo-9H-pyrido[2,3-b]indole and its isomer7-bromo-9H-pyrido[2,3-b]indole, which were brought on to the next stepdirectly.

Step 5—Tert-Butyl 5-bromo-9H-pyrido[2,3-b]indole-9-carboxylate

To a mixture of 5-bromo-9H-pyrido[2,3-b]indole and7-bromo-9H-pyrido[2,3-b]indole (10.0 g, 40.0 mmol) in THF/H₂O (100mL/100 mL) was added Boc₂O (17.4 g, 80.0 mmol) and NaOH (4.8 g, 120.0mmol), and the mixture was stirred at rt for 3 h. On completion, themixture was poured into the water (200 mL), and extracted with EA (2×100mL). The organic layers were washed with brine (2×100 mL), dried overNa₂SO₄, filtered and the filtrate was concentrated to give crude productwhich was purification by column chromatography to give tert-butyl5-bromo-9H-pyrido[2,3-b]indole-9-carboxylate (4.10 g, 7% yield for twosteps) as brown product. LC/MS (ESI, m/z): [M+1]⁺=348.2.

Step 6—5-Bromo-9H-pyrido[2,3-b]indole

A mixture of tert-butyl 5-bromo-9H-pyrido[2,3-b]indole-9-carboxylate(9.0 g, 25.9 mmol) in DCM (20 mL) was added TFA (15 mL), and the mixturewas stirred at rt for 16 h. On completion, the mixture was concentratedto give the title product (6.0 g, 94% yield) as brown solid.

Step7—3-(5-Bromopyrido[2,3-b]indol-9-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

To a mixture of 5-bromo-9H-pyrido[2,3-b]indole (250 mg, 1.01 mmol) and18-crown-6 (53 mg, 0.2 mmol) in THF (5 mL) was added NaHMDS (0.75 mL,1.5 mmol) (2 M in THF) at −30° C. After stirring for 1 h at −30° C., asolution of[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate(579 mg, 1.5 mmol) in THF (2 mL) was added into the above mixturedropwise at −30° C. The reaction mixture was stirred at −30° C. for 2 h.On completion, the mixture was quenched with NH₄Cl aqueous, thenextracted with EA The combined EA layers were concentrated and purifiedby reverse phase (0.10% FA) to give the title compound (286 mg, 60%yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (dd, J=1.2,7.6 Hz, 1H), 8.59-8.46 (m, 1H), 7.57-7.50 (m, 1H), 7.49-7.42 (m, 1H),7.41-7.35 (m, 1H), 7.33-7.23 (m, 2H), 7.22-7.05 (m, 1H), 6.94-6.86 (m,2H), 6.32-5.97 (m, 1H), 4.92-4.75 (m, 2H), 3.75 (s, 3H), 3.24-3.06 (m,2H), 2.97-2.84 (m, 1H), 2.27-2.15 (m, 1H).

Step 8—3-(5-Bromopyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-(5-bromopyrido[2,3-b]indol-9-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione(6.0 g, 12.5 mmol) in toluene (50 mL) was added MsOH (10 mL). Thereaction mixture was stirred at 110° C. for 4 h. On completion, themixture was quenched with water (20 mL), then extracted with EA (2×20mL). The organic layers were concentrated under reduced pressure. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 38%-68%, 10min) to give the title compound (2.8 g, 62% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.19 (s, 1H), 8.91 (dd, J=7.8, 1.5 Hz, 1H),8.53 (dd, J=4.7, 1.3 Hz, 1H), 7.72 (br s, 1H), 7.54-7.53 (m, 1H),7.49-7.45 (m, 1H), 7.38 (dd, J=7.9, 4.8 Hz, 1H), 6.19-6.00 (m, 1H),3.16-2.98 (m, 2H), 2.74-2.67 (m, 1H), 2.17-2.14 (m, 1H); LC/MS (ESI,m/z): [M+1]⁺=358.0/360.0.

3-[5-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(Intermediate XG)

Step 1—Tert-Butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

A mixture of 3-(5-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(270 mg, 0.75 mmol), tert-butyl(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (270 mg, 2.25 mmol,Intermediate IT) Cs₂CO₃ (270 mg, 2.25 mmol), PdCl₂(PPh₃)₂ (105 mg, 0.15mmol) and CuI (14 mg, 0.075 mmol) in DMF (10 mL) was stirred at 80° C.for 1 h under N₂ with microwave. The mixture was cooled to rt, pouredinto water (100 mL), extracted with EtOAc (3×100 mL). The combinedorganic layers were concentrated under reduced pressure, the residue waspurified by column chromatography on silica gel (petroleum ether:ethylacetate=2:1) to give the title product (180 mg, 41% yield) as a whitesolid. LC/MS (ESI, m/z): [M+1]⁺=360.28. ¹H NMR (400 MHz, DMSO-d₆) δ11.18 (s, 1H), 8.81 (dd, J=7.8, 1.6 Hz, 1H), 8.50 (dd, J=4.8, 1.7 Hz,1H), 7.73-7.68 (m, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.45-7.28 (m, 2H),6.80-6.76 (m, 1H), 6.08 (s, 1H), 4.65 (s, 2H), 3.81-3.70 (m, 2H), 3.62(dd, J=5.7, 3.6 Hz, 2H), 3.43 (t, J=6.1 Hz, 2H), 3.17-2.96 (m, 3H),2.76-2.64 (m, 1H), 2.50-2.45 (m, 1H), 2.17-2.13 (m, 1H), 1.35 (s, 9H).

Step 2—Tert-Butyl(2-(2-(3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-5-yl)propoxy)ethoxy)ethyl)carbamate

To a mixture of tert-butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(180 mg, 0.34 mmol), Pd/C (100 mg) in EA (10 mL) was stirred at rt underH₂ for 16 h. The mixture was filtered and the solid was washed with EA,the filtrate was concentrated under reduced pressure. Then the residuewas purified by column chromatography on silica gel (petroleumether:ethyl acetate=2:1) to give the title compound (100 mg, 56% yield)as a white solid. LC/MS (ESI, m/z): [M+1]⁺=525.1. ¹H NMR (400 MHz,DMSO-d₆) δ 11.15 (s, 1H), 8.54 (dd, J=7.9, 1.5 Hz, 1H), 8.42 (dd, J=4.9,1.5 Hz, 1H), 7.52-7.40 (m, 2H), 7.28 (dd, J=7.8, 4.9 Hz, 1H), 7.11 (d,J=7.4 Hz, 1H), 6.77-6.74 (m, 1H), 6.10-6.00 (m, 1H), 3.61-3.50 (m, 6H),3.43 (t, J=6.1 Hz, 2H), 3.23-3.20 (m, 2H), 3.12-2.96 (m, 4H), 2.72-2.65(m, 1H), 2.12-2.06 (m, 1H), 1.99-1.89 (m, 2H), 1.34 (s, 9H).

Step3—3-[5-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-5-yl]propoxy]ethoxy]ethyl]carbamate (100 mg, 190 umol) in DCM (2 mL) was added TFA(1.54 g, 13.5 mmol, 1 mL). The reaction mixture was stirred at 25° C.for 2 hrs. On completion, the mixture was concentrated in vacuo to givethe title compound (100 mg, 97% yield, TFA) as a white solid. LC-MS(ESI⁺) m/z 425.2 (M+H)⁺.

Tert-Butyl N-methyl-N-(1-prop-2-ynyl-4-piperidyl)carbamate (IntermediateXH)

To a solution of tert-butyl N-methyl-N-(4-piperidyl)carbamate (1.50 g,7.00 mmol, CAS #108612-54-0) and 3-bromoprop-1-yne (915 mg, 7.70 mmol,663 uL, CAS #106-96-70) in THF (30 mL) was added K₂CO₃ (2.90 g, 21.0mmol). The reaction mixture was stirred at 25° C. for 16 hrs. Oncompletion, the mixture was diluted with water (30 mL) and extractedwith EA (3×80 mL). The combined organic layers was dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (1.50 mg,85% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 4.16-3.61 (m, 1H),3.29 (d, J=2.0 Hz, 2H), 3.01-2.90 (m, 2H), 2.73 (s, 3H), 2.35-2.21 (m,3H), 1.81-1.72 (m, 2H), 1.69-1.63 (m, 2H), 1.46 (s, 9H).

3-[3-Methyl-4-[3-[4-(methylamino)-1-piperidyl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate XI)

Step 1—Tert-ButylN-[1-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-4-piperidyl]-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-(1-prop-2-ynyl-4-piperidyl)carbamate (559 mg, 2.22 mmol,Intermediate XH) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP) in DMF (5 mL) was added Pd(PPh₃)₂Cl₂(103 mg, 147 umol), CuI (28.1 mg, 147 umol) and Cs₂CO₃ (955 mg, 2.93mmol, 2.58 mL). The reaction mixture was stirred at 80° C. for 2 hrunder N₂. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (700 mg,93% yield) as a gray solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H),7.20-6.93 (m, 3H), 5.40(dd, J=5.2, 12.8 Hz, 1H), 3.66 (s, 3H), 3.58 (s,2H), 2.98-2.84 (m, 3H), 2.68 (s, 3H), 2.66-2.59 (m, 2H), 2.25 (t, J=10.8Hz, 2H), 2.07-1.99 (m, 1H), 1.75-1.50 (m, 5H), 1.40 (s, 9H); LC-MS(ESI⁺) m/z 510.3 (M+H)⁺.

Step 2—Tert-ButylN-[1-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]-4-piperidyl]-N-methyl-carbamate

To a solution of tert-butylN-[1-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]-4-piperidyl]-N-methyl-carbamate (650 mg, 1.28 mmol) in THF(20 mL) was added Pd/C (150 mg, 1.28 mmol, 10 wt %) and Pd(OH)₂/C (150mg, 10 wt %). The reaction mixture was stirred at 25° C. under H₂ (15psi) for 2 hrs. On completion, the residue was filtered and the filtratewas concentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (480 mg,73% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),6.96 (d, J=4.8 Hz, 2H), 6.93-6.86 (m, 1H), 5.36 (dd, J=5.6, 12.8 Hz,1H), 3.93-3.65 (m, 1H), 3.56 (s, 3H), 3.08-2.97 (m, 2H), 2.96-2.81 (m,3H), 2.76-2.67 (m, 1H), 2.66 (s, 3H), 2.64-2.58 (m, 1H), 2.49-2.39 (m,2H), 2.14-2.05 (m, 2H), 2.03-1.94 (m, 1H), 1.83-1.62 (m, 4H), 1.56-1.48(m, 2H), 1.39 (s, 9H); LC-MS (ESI⁺) m/z 514.3 (M+H)⁺.

Step3—3-[3-Methyl-4-[3-[4-(methylamino)-1-piperidyl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[1-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]-4-piperidyl]-N-methyl-carbamate (100 mg, 194 umol) in DCM (2 mL)was added HCl/dioxane (4 M, 1 mL). The reaction mixture was stirred at20° C. for 2 hrs. On completion, the mixture was concentrated in vacuoto give the title compound (85.0 mg, 97% yield, HCl) as a white solid.LC-MS (ESI⁺) m/z 414.3 (M+H)⁺.

Tert-Butyl N-methyl-N-[2-(4-piperidylmethoxy) ethyl]carbamate(Intermediate XJ)

Step 1—Benzyl 4-((2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate

A solution of benzyl 4-(hydroxymethyl) piperidine-1-carboxylate (15.0 g,60.2 mmol, CAS #122860-33-7) in DCM (15 mL) was added diacetoxyrhodium(1.33 g, 3.01 mmol, CAS #623-73-4). The mixture was stirred at 25° C.for 0.5 hour. Then ethyl 2-diazoacetate (13.7 g, 120 mmol) in DCM (15mL) was added dropwise slowly to the solution. The mixture was stirredat 25° C. for 12 hours. On completion, the reaction mixture was quenchedby water (10 mL), and extracted with DCM (3×20 mL). The combined organiclayers dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography to give thetitle compound (16.8 g, 83% yield) as yellow oil. LC-MS (ESI⁺) m/z 336.2(M+H)⁺.

Step 2—Benzyl 4-((2-hydroxyethoxy)methyl)piperidine-1-carboxylate

To a solution of benzyl4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylate (16.8 g, 50.1mmol) in THF (180 mL) was added LiBH₄ (2.18 g, 100 mmol) at 0° C. Themixture was stirred at 25° C. for 12 hours. On completion, the reactionmixture was quenched with H₂O (200 mL) and then extracted with ethylacetate (2×300 mL). Then the organic layers were washed with brine(2×150 mL). The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by column chromatography to give the title compound (13.2 g,90% yield) as colorless oil. LC-MS (ESI⁺) m/z 294.2 (M+H)⁺.

Step 3—Benzyl 4-((2-azidoethoxy)methyl)piperidine-1-carboxylate

To a solution of benzyl4-(2-hydroxyethoxymethyl)piperidine-1-carboxylate (4.00 g, 13.6 mmol) intoluene (40 mL) was added DPPA (4.50 g, 16.4 mmol) and DBU (2.49 g, 16.4mmol). The mixture was stirred at 100° C. for 12 hours. On completion,the reaction mixture was diluted with H₂O (50 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (4.34 g, 98% yield) as yellow oil.

Step 4—Benzyl 4-(2-aminoethoxymethyl)piperidine-1-carboxylate

To a solution of benzyl 4-(2-azidoethoxymethyl)piperidine-1-carboxylate(4.34 g, 13.6 mmol) in a mixed solvent of THF (45 mL) and H₂O (5 mL) wasadded PPh₃ (3.58 g, 13.6 mmol). The mixture was stirred at 66° C. for 12hours. On completion, the reaction mixture was diluted with H₂O (50 mL)and extracted with ethyl acetate (3×50 mL). The organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (3.99 g, 99% yield) as yellow oil. LC-MS (ESI⁺) m/z293.2 (M+H)⁺.

Step 5—Benzyl4-[2-(tert-butoxycarbonylamino)ethoxymethyl]piperidine-1-carboxylate

To a solution of benzyl 4-(2-aminoethoxymethyl)piperidine-1-carboxylate(3.99 g, 13.7 mmol) in THF (40 mL) was added Boc₂O (4.47 g, 20.5 mmol)and TEA (4.14 g, 40.9 mmol). The mixture was stirred at 25° C. for 12hours. On completion, the reaction mixture was diluted with H₂O (100 mL)and extracted with (2×100 mL). The organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by column chromatography to give the titlecompound (4.70 g, 80% yield) as yellow oil. LC-MS (ESI⁺) m/z 415.3(M+Na)⁺.

Step 6—Benzyl4-[2-[tert-butoxycarbonyl(methyl)amino]ethoxymethyl]piperidine-1-carboxylate

To a solution of benzyl4-[2-(tert-butoxycarbonylamino)ethoxymethyl]piperidine-1-carboxylate(4.60 g, 11.7 mmol) in DMF (50 mL) was added NaH (938 mg, 23.4 mmol, 60%dispersion in oil) at 0° C. Then CH₃I (3.33 g, 23.4 mmol) was addeddropwise to the solution. The mixture was stirred at 0-25° C. for 2hours. On completion, the reaction mixture was quenched with saturatedNH₄Cl (20 mL). Then H₂O (50 mL) and ethyl acetate (100 mL) was added.The aqueous layer was extracted with ethyl acetate (2×100 mL). Thecombined organic layers were washed with brine (50 mL). The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give a residue. The residue was purified by columnchromatography to give the title compound (3.80 g, 79% yield) as yellowoil.

Step 7—Tert-Butyl N-methyl-N-[2-(4-piperidylmethoxy) ethyl]carbamate

To a solution of benzyl4-[2-[tert-butoxycarbonyl(methyl)amino]ethoxymethyl]piperidine-1-carboxylate(3.80 g, 9.35 mmol) in MeOH (80 mL) was added Pd/C (400 mg, 377 umol, 10wt %). The mixture was stirred at 25° C. for 12 hours. On completion,the reaction mixture was filtered and concentrated in vacuo to give thetitle compound (3.30 g, 98% yield) as yellowish oil. LC-MS (ESI⁺) m/z273.2 (M+H)⁺.

3-(3-methyl-5-(4-((2-(methylamino)ethoxy)methyl)piperidin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionemethanesulfonate (Intermediate XK)

Step 1—Tert-ButylN-methyl-N-[2-[[1-[3-(methylamino)-4-nitro-phenyl]-4-piperidyl]methoxy]ethyl]carbamate

To a solution of tert-butylN-methyl-N-[2-(4-piperidylmethoxy)ethyl]carbamate (3.30 g, 12.1 mmol,Intermediate XJ) in DMF (30 mL) was added5-fluoro-N-methyl-2-nitro-aniline (2.06 g, 12.1 mmol) and K₂CO₃ (5.02 g,36.4 mmol). Then the mixture was stirred at 80° C. for 12 hours. Oncompletion, the reaction mixture was diluted with H₂O (50 mL) andextracted with ethyl acetate (3×100 mL). The organic layers were washedwith brine (3×50 mL). Then the organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography to give the title compound(4.40 g, 85% yield) as orange oil. LC-MS (ESI⁺) m/z 423.5 (M+H)⁺.

Step 2—Tert-Butyl(2-((1-(4-amino-3-(methylamino)phenyl)piperidin-4-yl)methoxy)ethyl)(methyl)carbamate

To a solution of tert-butylN-methyl-N-[2-[[1-[3-(methylamino)-4-nitro-phenyl]-4-piperidyl]methoxy]ethyl]carbamate (3.6 g, 8.52 mmol) in MeOH (100 mL) was addedPd/C (0.7 g, 10 wt %) under N₂. The suspension was degassed in vacuo andpurged with H₂ three times. The mixture was stirred under H₂ (15 Psi) at25° C. for 4 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the title compound (3.2 g, 97% yield) asbrown oil. ¹H NMR (400 MHz, CDCl₃) δ 6.63 (d, J=8.2 Hz, 1), 6.34 (d,J=2.4 Hz, 1H), 6.28 (dd, J=2.6, 8.2 Hz, 1H), 3.52 (d, J=12.0 Hz, 4H),3.45-3.31 (m, 4H), 2.93 (s, 3H), 2.86 (s, 3H), 2.62 (dt, J=2.0, 11.6 Hz,2H), 1.83 (d, J=12.6 Hz, 2H), 1.73-1.60 (m, 1H), 1.49-1.40 (m, 11H);LC-MS (ESI⁺) m/z 393.2 (M+H)⁺.

Step 3—Tert-Butyl(2-((1-(4-amino-3-(methylamino)phenyl)piperidin-4-yl)methoxy)ethyl)(methyl)carbamate

To a mixture of tert-butylN-[2-[[1-[4-amino-3-(methylamino)phenyl]-4-piperidyl]methoxy]ethyl]-N-methyl-carbamate (1.5 g, 3.82 mmol) in MeCN (30 mL) was addedCDI (1.24 g, 7.64 mmol) under N₂. The mixture was stirred for at 85° C.16 hours. On completion, the reaction mixture was concentrated in vacuoto remove THF. The residue was diluted with water (20 mL) and extractedwith EA (3×20 mL). The combined organic layers was dried over Na₂SO₄,filtered and concentrated in vacuo to give a residue. The residue waspurified by reverse phase (FA condition) to give the title compound(1.10 g, 69% yield) as a purple solid. ¹H NMR (400 MHz, CDCl₃) δ 9.06(s, 1), 6.95 (d, J=8.4 Hz, 1), 6.74-6.69 (m, 1), 6.62 (d, J=2.2 Hz, 1H),3.60-3.52 (m, 4H), 3.39 (s, 3H), 3.37-3.31 (m, 2H), 2.93 (s, 3H),2.73-2.65 (m, 2H), 1.86 (d, J=11.8 Hz, 2H), 1.77-1.67 (m, 2H), 1.47-1.33(m, 13H; LC-MS (ESI⁺) m/z 419.2 (M+H)⁺.

Step 4—Tert-Butyl(2-((1-(4-amino-3-(methylamino)phenyl)piperidin-4-yl)methoxy)ethyl)(methyl)carbamate

To a mixture of tert-butylN-methyl-N-[2-[[1-(3-methyl-2-oxo-1H-benzimidazol-5-yl)-4-piperidyl]methoxy]ethyl]carbamate(1.10 g, 2.63 mmol) in THF (20 mL) was added t-BuOK (442 mg, 3.94 mmol)at 0° C. under N₂. Then a solution of[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (1.50 g, 3.94 mmol, Intermediate IQ) in THF(20 mL) was added dropwise at 0° C. The mixture was warmed slowly to 25°C. and stirred at 25° C. for 24 hours. On completion, the reactionmixture was quenched by addition water (10 mL) at 25° C., and thenextracted with EA (3×20 mL). The combined organic layers, dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by column chromatography to give the title compound(800 mg, 24% yield) as brown oil. LC-MS (ESI⁺) m/z 650.2 (M+H)⁺.

Step5—3-(3-methyl-5-(4-((2-(methylamino)ethoxy)methyl)piperidin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionemethanesulfonate

To a mixture of tert-butylN-[2-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]-4-piperidyl]methoxy]ethyl]-N-methyl-carbamate(500 mg, 769 umol) in toluene (10 mL) was added CH₃SO₃H (2.22 g, 23.1mmol) at 25° C. The mixture was stirred at 120° C. for 3 hours. Oncompletion, the reaction mixture was quenched by addition water (2 mL)at 25° C., and then neutralized by adding NEt₃ to pH=5. Then the mixturewas filtered and concentrated in vacuo to give a residue. The residuewas purified by reverse phase (FA condition) to give the title compound(100 mg, 25% yield, CH₃SO₃H) as yellow oil. LC-MS (ESI⁺) m/z 430.1(M+H)⁺.

Tert-Butyl 4-(2-prop-2-ynoxyethyl)piperazine-1-carboxylate (IntermediateXL)

A mixture of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.00g, 21.7 mmol, CAS #77279-24-4), 3-bromoprop-1-yne (2.58 g, 21.7 mmol,CAS #106-96-7) in THF (35 mL) was added TBAI (802 mg, 2.17 mmol), KI(541 mg, 3.26 mmol) and KOH (1.22 g, 21.7 mmol). The mixture was stirredat 25° C. for 12 hrs under N₂ atmosphere. On completion, the reactionmixture was diluted with water (2×100 mL) and extracted with ethylacetate (3×100 mL). The combined organic layers were washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, PE:EA=10:1 to 3:1) to give the title compound(1.30 g, 18% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.12 (d,J=2.4 Hz, 2H), 3.54 (t, J=5.6 Hz, 2H), 3.41 (s, 1H), 3.30-3.26 (m, 4H),2.49-2.47 (m, 2H), 2.36-2.33 (m, 4H), 1.39 (s, 9H).

3-[3-Methyl-2-oxo-4-[3-(2-piperazin-1-ylethoxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate XM)

Step 1—Tert-Butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethyl]piperazine-1-carboxylate

A mixture of tert-butyl 4-(2-prop-2-ynoxyethyl)piperazine-1-carboxylate(476 mg, 1.77 mmol, Intermediate XL),3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300mg, 887 umol, Intermediate HP), Cs₂CO₃ (1.45 g, 4.44 mmol), 4Å molecularsieves (50 mg), Pd(PPh₃)₂Cl₂ (124 mg, 177 umol) and CuI (33.8 mg, 177umol) in DMF (8 mL) under N₂ atmosphere. The mixture was de-gassed andthen heated at 80° C. for 2 hrs. On completion, the reaction mixture wasconcentrated in vacuo. The crude product was purified by reversed-phaseHPLC (0.1% FA condition) to give the title compound (400 mg, 77% yield)as brown oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 7.19 (d, J=7.2Hz, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.06-6.94 (m, 1H), 5.41 (dd, J=4.8,12.4 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 2H), 3.64 (s, 3H), 3.56-3.52 (m,4H), 2.94-2.89 (m, 1H), 2.85-2.71 (m, 4H), 2.63-2.58 (m, 4H), 2.09-1.97(m, 1H), 1.39 (s, 9H); LC-MS (ESI⁺) m/z 526.3 (M+H)⁺.

Step 2—Tert-butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethyl]piperazine-1-carboxylate

To a solution of tert-butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethyl]piperazine-1-carboxylate(400 mg, 679 umol) in THF (20 mL) was added Pd/C (50.0 mg, 10 wt %) andPd(OH)₂ (50.0 mg) under N₂ atmosphere. The mixture was stirred at 25° C.for 12 hrs under H₂ (15 Psi). On completion, the reaction mixture wasconcentrated in vacuo. The product was filtered under reduced pressureto give the title compound (395 mg, 99% yield) as brown solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 6.97 (d, J=5.2 Hz, 2H), 6.90-6.85(m, 1H), 5.37 (dd, J=5.2, 12.4 Hz, 1H), 4.26 (t, J=7.2 Hz, 1H), 4.15 (t,J=6.5 Hz, 1H), 3.69-3.62 (m, 2H), 3.56 (s, 3H), 3.50-3.45 (m, 4H),2.98-2.95 (m, 2H), 2.75-2.71 (m, 2H), 2.69-2.66 (m, 2H), 2.65-2.59 (m,4H), 2.19-2.13 (m, 1H), 1.88-1.82 (m, 2H), 1.77-1.71 (m, 1H), 1.40 (s,9H). LC-MS (ESI⁺) m/z 530.3 (M+H)⁺.

Step3—3-[3-Methyl-2-oxo-4-[3-(2-piperazin-1-ylethoxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethyl]piperazine-1-carboxylate(100 mg, 189 umol) in DCM (4 mL) was added HCl/dioxane (2 mL). Themixture was stirred at 25° C. for 2 hrs. On completion, the reactionmixture was concentrated in vacuo to give the title compound (87 mg, 58%yield, HCl) as brown solid. LC-MS (ESI⁺) m/z 430.3 (M+H)⁺.

Tert-Butyl N-isopropyl-N-(3-prop-2-ynoxypropyl)carbamate (IntermediateXN)

Step 1—3-(Isopropylamino)propan-1-ol

A solution of 3-bromopropan-1-ol (5.00 g, 36.0 mmol) in propan-2-amine(6.19 g, 105 mmol) was stirred at 50° C. for 12 hours. On completion,the mixture was concentrated to give the title compound (7.00 g, 90%yield, 50% purity) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.84 (t,J=5.6 Hz, 2H), 3.40-3.33 (m, 1H), 3.12 (t, J=6.4 Hz, 2H), 2.11-1.99 (m,2H), 1.39 (d, J=6.6 Hz, 6H).

Step 2—Tert-Butyl N-(3-hydroxypropyl)-N-isopropyl-carbamate

To a solution of 3-(isopropylamino)propan-1-ol (7.00 g, 30.0 mmol, 50%purity) in DCM (10 mL) was added (Boc)₂O (13.0 g, 59.7 mmol, 13.7 mL)and Et₃N (8.00 g, 79.0 mmol) at 15° C. The mixture was stirred at 15° C.for 6 hours. On completion, the mixture was concentrated in vacuo. Theresidue was purified by flash silica gel chromatography to give thetitle compound (3.60 g, 50% yield) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 3.58 (m, 2H), 3.35 (m, 2H), 1.67 (m, 2H), 1.48 (s, 9H), 1.16(d, J=6.8 Hz, 6H), 0.91-0.86 (m, 1H).

Step 3—Tert-Butyl N-isopropyl-N-(3-prop-2-ynoxypropyl)carbamate

To a solution of tert-butyl N-(3-hydroxypropyl)-N-isopropyl-carbamate(3.40 g, 15.7 mmol) and TBAI (57.8 mg, 156 umol) in THF (100 mL) wasadded NaH (750 mg, 18.7 mmol, 60% dispersion in oil) at 0° C. Themixture was stirred at 0° C. for 0.5 hour. 3-bromoprop-1-yne (2.79 g,23.5 mmol) was added at 0° C. The mixture was stirred at 0-15° C. for 6hours. On completion, the reaction mixture was quenched with sat. aq.NH₄Cl (30 mL) at 0° C. The mixture was extracted with EA (3×100 mL). Thecombined organic layers were washed with brine (100 ml), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash silica gel chromatography to give the title compound (3.50 g, 80%yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.13 (d, J=2.4 Hz, 2H),3.53 (t, J=6.4 Hz, 2H), 3.14 (m, 2H), 2.41 (t, J=2.4 Hz, 1H), 1.86-1.77(m, 2H), 1.46 (s, 9H), 1.12 (d, J=6.8 Hz, 6H), 0.90-0.80 (m, 1H).

3-[4-[3-[3-(Isopropylamino)propoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate XO)

Step 1—Tert-ButylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]propyl]-N-isopropyl-carbamate

To a solution of tert-butylN-isopropyl-N-(3-prop-2-ynoxypropyl)carbamate (755 mg, 2.96 mmol,Intermediate XN) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HP) in DMF (10 mL) was added Pd(dppf)Cl₂(173 mg, 237 umol) and Cs₂CO₃ (1.54 g, 4.73 mmol) and CuI (45.1 mg, 237umol) at 20° C. The mixture was stirred at 80° C. for 2 hours under N₂.On completion, the mixture was filtered through celite and the filtratewas concentrated in vacuo. The residue was purified by reversed-phaseHPLC (FA condition) to give the title compound (350 mg, 55% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 7.18 (d, J=7.6Hz, 1H), 7.14-7.10 (m, 1), 7.08-6.99 (m, 1H), 5.43-5.38 (m, 1H), 4.44(s, 2H), 3.09 (m, 2H), 2.95-2.84 (m, 1H), 2.09-1.97 (m, 1H), 1.82-1.69(m, 2H), 1.38 (s, 9H), 1.08 (d, J=6.0 Hz, 6H).

Step 2—Tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]propyl]-N-isopropyl-carbamate

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]propyl]-N-isopropyl-carbamate (350 mg, 683 umol) in THF (20mL) was added Pd(OH)₂/C (350 mg, 683 umol, 10 wt %) and Pd/C (350 mg,682 umol, 10 wt %). The mixture was stirred at 15° C. for 2 hours. Oncompletion, the mixture was filtered with celite and the filtrate wasconcentrated in vacuo to give the title compound (350 mg, 99% yield) asyellow oil. LC-MS (ESI⁺) m/z 539.4 (M+23)+

Step3—3-[4-[3-[3-(Isopropylamino)propoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]propyl]-N-isopropyl-carbamate (320 mg, 619 umol) in DCM (4 mL)was added TFA (10.7 mL) at 15° C. The mixture was stirred at 15° C. for0.5 hour. On completion, the mixture was concentrated in vacuo to givethe title compound (320 mg, 97% yield, TFA salt) as yellow oil. LC-MS(ESI⁺) m/z 417.3 (M+H)⁺.

Tert-Butyl N-cyclopropyl-N-(3-prop-2-ynoxypropyl)carbamate (IntermediateXP)

Step 1—3-(Cyclopropylamino)propan-1-ol

A mixture of 3-bromopropan-1-ol (5.00 g, 35.9 mmol, 3.25 mL, CAS#627-18-9) in cyclopropanamine (10.2 g, 179 mmol, 12.4 mL, CAS#765-30-0) was stirred at 50° C. for 12 hours. On completion, thereaction mixture was concentrated in vacuo to give the title compound(4.00 g, 96% yield) as light yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ3.45 (t, J=6.0 Hz, 2H), 3.01 (t, J=7.6 Hz, 2H), 2.75-2.68 (m, 1H),1.81-1.73 (m, 2H), 0.88-0.82 (m, 2H), 0.74-0.70 (m, 2H).

Step 2—Tert-Butyl N-cyclopropyl-N-(3-hydroxypropyl)carbamate

To a mixture of 3-(cyclopropylamino)propan-1-ol (4.00 g, 34.7 mmol) inDCM (60 mL) was added TEA (10.5 g, 104 mmol, 14.5 mL) and Boc₂O (15.1 g,69.4 mmol, 15.9 mL). The reaction mixture was stirred at 25° C. for 12hours. On completion, the reaction mixture was diluted with water (30mL) and extracted with EA (3×50 mL). The combined organic layers wasdried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by column chromatography to give the titlecompound (3.70 g, 49% yield) as light yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 3.54 (d, J=5.0 Hz, 2H), 3.36 (t, J=6.0 Hz, 2H), 2.49-2.41 (m,1H), 1.74-1.65 (m, 2H), 1.45 (s, 9H), 0.75-0.68 (m, 2H), 0.62-0.55 (m,2H).

Step 3—Tert-Butyl N-cyclopropyl-N-(3-prop-2-ynoxypropyl)carbamate

To a mixture of tert-butyl N-cyclopropyl-N-(3-hydroxypropyl)carbamate(3.20 g, 14.8 mmol) in THF (30 mL) was added NaH (1.19 g, 29.7 mmol, 60%dispersion in oil) at 0° C. for 0.5 hour. Then 3-bromoprop-1-yne (3.54g, 29.7 mmol, 2.56 mL) was added to the mixture. The reaction mixturewas stirred at 25° C. for 12 hours. On completion, the reaction mixturewas quenched with sat. NH₄Cl solution (10 mL) under stirring. Themixture was diluted with water (30 mL) and extracted with EA (3×50 mL).The combined organic layers was dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (3.70 g, 98% yield) aslight yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.13 (d, J=2.4 Hz, 2H), 3.53(t, J=6.4 Hz, 2H), 3.32-3.25 (m, 2H), 2.54-2.46 (m, 1H), 2.41 (t, J=2.4Hz, 1H), 1.89-1.81 (m, 2H), 1.45 (s, 9H), 0.75-0.70 (m, 2H), 0.61-0.57(m, 2H).

3-[4-[3-[3-(Cyclopropylamino)propoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate XQ)

Step 1—Tert-ButylN-cyclopropyl-N-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]propyl]carbamate

To a mixture of tert-butylN-cyclopropyl-N-(3-prop-2-ynoxypropyl)carbamate (599 mg, 2.37 mmol,Intermediate XP) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HP) in DMF (5 mL) was added CuI (22.5 mg,118 umol), Cs₂CO₃ (1.93 g, 5.91 mmol), Pd(PPh₃)₂Cl₂ (83.0 mg, 118 umol)and 4Å molecular sieves (10 mg). The reaction mixture was stirred at 80°C. for 2 hours under N₂ atmosphere. On completion, the reaction mixturewas filtered and concentrated in vacuo. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (240 mg,39% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H),7.18 (d, J=7.6 Hz, 1H), 7.13-7.09 (m, 1H), 7.05-7.00 (m, 1H), 5.43-5.37(m, 1H), 4.43 (s, 2H), 3.64 (s, 3H), 3.53 (t, J=6.3 Hz, 2H), 3.44-3.37(m, 2H), 3.21 (t, J=7.2 Hz, 2H), 2.94-2.83 (m, 1H), 2.75-2.55 (m, 3H),2.07-1.98 (m, 1H), 1.80-1.70 (m, 2H), 1.39 (s, 2H), 1.37 (s, 9H),0.70-0.63 (m, 2H), 0.57-0.49 (m, 2H).

Step 2—Tert-ButylN-cyclopropyl-N-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]propyl]carbamate

To a mixture of tert-butylN-cyclopropyl-N-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]propyl]carbamate(180 mg, 352 umol) in THF (20 mL) was added Pd(OH)₂/C (30.0 mg, 10 wt %)and Pd/C (30.0 mg, 10 wt %). The reaction mixture was stirred at 25° C.for 2.5 hours under H₂ (15 Psi) atmosphere. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (181 mg, 99% yield) as light yellow solid. The residue was usedto the next step directly without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 6.96 (d, J=4.4 Hz, 2H), 6.89-6.84 (m, 1H),5.39-5.33 (m, 1H), 3.56 (s, 3H), 3.41 (d, J=6.0 Hz, 2H), 3.38 (t, J=6.0Hz, 2H), 3.21 (t, J=7.2 Hz, 2H), 2.99-2.93 (m, 2H), 2.91-2.84 (m, 1H),2.72-2.62 (m, 3H), 2.02-1.99 (m, 1H), 1.85-1.79 (m, 2H), 1.77-1.70 (m,2H), 1.38 (s, 9H), 0.70-0.64 (m, 2H), 0.56-0.50 (m, 2H).

Step3—3-[4-[3-[3-(Cyclopropylamino)propoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butylN-cyclopropyl-N-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]propyl]carbamate(190 mg, 369 umol) in DCM (1 mL) was added TFA (4.62 g, 40.5 mmol, 3.00mL). The reaction mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (195 mg, 99% yield, TFA salt) as red oil. LC-MS (ESI⁺)m/z 415.3 (M+H)⁺.

Tert-Butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate (IntermediateXS)

Step 1—Tert-Butyl 4-(4-pyridylmethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-methylenepiperidine-1-carboxylate (6.00 g,30.4 mmol, CAS #159635-49-1) was added 9-BBN THF solution (0.5 M, 60.5mL) at 25° C. The reaction mixture was stirred at 80° C. for 1 hourunder N₂. After cooling to 25° C., 4-bromopyridine (4.33 g, 27.4 mmol,CAS #1120-87-2), K₂CO₃ (5.04 g, 36.5 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (683 mg,836 umol), DMF (50 mL) and H₂O (5 mL) were added to the reaction mixturewas added. The reaction mixture was stirred at 60° C. for 3 hours. Aftercooling to 25° C., another charge of Pd(dppf)Cl₂·CH₂Cl₂ (683 mg, 836umol) was added to the reaction mixture. The mixture was stirred at 60°C. for 24 hours. On completion, the mixture was cooled to 25° C. andpoured into water (60 mL). The pH was adjusted to 11 with 10% aq. NaOH.The mixture was extracted with ethyl acetate (2×100 mL). The combinedorganic layers were dried over NaSO₄, filtered and concentrated invacuo. The residue was purified by column chromatography to give thetitle compound (5.80 g, 76% yield) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 8.53-8.47 (m, 2H), 7.08 (d, J=6.0 Hz, 2H), 2.64 (t, J=12.0 Hz,2H), 2.54 (d, J=7.6 Hz, 2H), 1.77-1.64 (m, 2H), 1.63-1.56 (m, 2H),1.54-1.47 (m, 1H), 1.45 (s, 9H), 1.21-1.09 (m, 2H).

Step 2 Tert-Butyl 4-(4-piperidylmethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(4-pyridylmethyl)piperidine-1-carboxylate(5.80 g, 20.9 mmol) in EtOH (100 mL) and HOAc (1.26 g, 20.9 mmol) wasadded PtO₂ (1.02 g, 4.48 mmol) at 20° C. The reaction mixture wasstirred at 20° C. for 54 hours under H₂ (50 Psi). On completion, thereaction mixture was filtered with celite and the filtrate wasconcentrated in vacuo to give the title compound (4.68 g, 79% yield) asblack oil. ¹H NMR (400 MHz, CDCl₃) δ 4.26-4.00 (m, 4H), 3.16 (d, J=9.6Hz, 2H), 2.70-2.60 (m, 3H), 1.69 (d, J=12.8 Hz, 2H), 1.65-1.56 (m, 2H),1.54-1.46 (m, 2H), 1.44 (s, 9H), 1.29-1.20 (m, 2H), 1.20-1.13 (m, 2H),1.11-0.97 (m, 2H); LC-MS (ESI⁺) m/z 283.0 (M+H)⁺.

3-[3-methyl-2-oxo-4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate XT)

Step 1-Tert-Butyl4-[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate

To a solution of tert-butyl4-(4-piperidylmethyl)piperidine-1-carboxylate (128 mg, 452 umol,Intermediate XS) in THF (10 mL) and DMF (5 mL) was added TEA (45.8 mg,452 umol). The mixture was stirred at 25° C. for 10 minutes. HOAc (27.2mg, 452 umol) and1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(195 mg, 679 umol, Intermediate WW) were added to the above mixture. Thereaction mixture was stirred at 25° C. for 20 minutes. Then NaBH(OAc)₃(192 mg, 905 umol) was added. The reaction mixture was stirred at 25° C.for 16 hours. On completion, the reaction was quenched with H₂O (1 mL).The mixture was concentrated in vacuo. The residue was purified byreverse phase (FA condition) to give the title compound (250 mg, 99%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),7.19 (d, J=6.4 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.86 (d, J=7.2 Hz, 1H),5.36 (d, J=5.6 Hz, 1H), 3.97-3.81 (m, 2H), 3.66 (s, 3H), 3.60 (s, 2H),2.96-2.83 (m, 2H), 2.83-2.69 (m, 4H), 2.66-2.58 (m, 3H), 2.06-1.89 (m,4H), 1.58 (d, J=12.4 Hz, 4H), 1.37 (s, 9H), 1.14-0.98 (m, 4H), 0.96-0.81(m, 2H); LC-MS (ESI⁺) m/z 554.4 (M+H)⁺.

Step2—3-[3-methyl-2-oxo-4-[[4-(4-piperidylmethyl)-1-piperidyl]methyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]methyl]piperidine-1-carboxylate(100 mg, 181 umol) in DCM (2 mL) was added 4 M HCl/dioxane (1 mL) at 25°C. The reaction mixture was stirred at 25° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby reverse phase (FA condition) to give the title compound (65.0 mg, 79%yield) as a white solid. LC-MS (ESI⁺) m/z 454.5 (M+H)⁺.

3-(7-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (IntermediateXU)

Step 1—3-bromo-N-(3-nitrophenyl)pyridin-2-amine

To a mixture of 3-bromopyridin-2-amine (5 g, 28.9 mmol),1-iodo-3-nitrobenzene (7.2 g, 28.9 mmol), Xanphos (1.07 g, 2.89 mmol),and Cs₂CO₃ (18.9 g, 57.8 mmol) in DMF (50 mL) was added Pd(OAc)₂ (323.7mg, 1.44 mmol). The mixture was degrassed with N₂ and stirred at 130° C.overnight. The reaction mixture was cooled to rt, poured into water, andextracted with EtOAc (3×200 mL). The combined organic layers was washedwith water (200 mL×2) and brine (200 mL×2), dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography eluting with EA/PE=20% to give the title compound (5.6 g,66% yield) as a light yellow solid. LC/MS (ESI, m/z): [M+1]⁺=294.0,296.0.

Step 2—7-nitro-9H-pyrido[2,3-b]indole

To a mixture of 3-bromo-N-(3-nitrophenyl)pyridin-2-amine (4 g, 6.78mmol), DCPHB (474 mg, 1.356 mmol), and DBU (4.12 g, 27.12 mmol) in DMA(12 mL) was added Pd(OAc)₂ (152 mg, 0.678 mmol). The mixture wasdegrassed with N₂ and stirred at 170° C. for 1 h. The reaction mixturewas cooled to rt, poured into water, and extracted with EtOAc (3×50 mL).The combined organic layers was washed with water (100 mL×2) and brine(100 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography eluting withEA/PE=1:1 to give the title compound (1 g, 34% yield) as a light yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.40 (s, 1H), 8.73-8.70 (m, 1H),8.60-8.58 (m, 1H), 8.44 (d, J=8.63 Hz, 1H), 8.33 (d, J=2.00 Hz, 1H),8.13-8.10 (m, 1H), 7.35 (dd, J=7.75, 4.75 Hz, 1H); LC/MS (ESI, m/z):[M+1]⁺=214.1.

Step3—1-(4-methoxybenzyl)-3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of 7-nitro-9H-pyrido[2,3-b]indole (910 mg, 4.27 mmol) inTHF (10 mL) and DMF (2 mL) was added t-BuOK (718 mg, 6.41 mmol) portionwise at 0° C. under N₂ atmosphere. After addition, the mixture wasstirred at 0° C.-5° C. for 1 h. Then1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate(2.44 g, 6.41 mmol) in THF (10 mL) was added dropwise at 0° C.-5° C.over 20 min. After addition, the reaction mixture was stirred at 0°C.-5° C. for an additional 1 h. The reaction mixture was quenched by theaddition of water, then extracted with EtOAc (3×20 mL). The combinedorganic layers was washed with brine (10 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was trituratedwith EtOAc and dried to give (1.3 g, 69% yield) as a light yellow solid.LC/MS (ESI, m/z): [M+1]⁺=445.2.

Step 4—3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of1-(4-methoxybenzyl)-3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(1.7 g, 3.83 mmol) in CH₃CN (20 mL) was added CAN (10.5 g, 19.15 mmol)in water (5 mL) at 0° C. dropwise. After addition, the mixture wasstirred at rt overnight. The mixture was poured into water (50 mL), thenextracted with EtOAc (3×50 mL). The combined organic layers was washedwith brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was triturated with EtOAc and driedto give the title compound (850 mg, 69% yield) as a light yellow solid.LC/MS (ESI, m/z): [M+1]⁺=325.2.

Step 5—3-(7-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-(7-nitro-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (850 mg, 2.62mmol) in EtOAc (15 mL) was added 10% palladium on activated carbon (170mg). The mixture was hydrogened at rt overnight. The reaction mixturewas filtered, the filtrate was concentrated in vacuo to give the titlecompound (764 mg, 99% yield) as a white solid. LC/MS (ESI, m/z):[M+1]⁺=295.2.

Step 6—3-(7-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-(7-amino-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (661 mg, 2.26mmol) in 40% HBr solution (10 mL) was added NaNO₂ (156 mg, 2.26 mmol)portion wise at 0° C. After addition, the mixture was stirred at 0° C.for 30 min. Then the diazonium solution was added dropwise to CuBr (972mg, 6.78 mmol) in 40% HBr solution (10 mL). The mixture was stirred atrt for 2 h. Then the mixture was poured into water (50 mL), basified topH>8 with saturated NaHCO₃ solution, then extracted with EtOAc (3×50mL). The combined organic layers was washed with brine (2×30 mL), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by prep-HPLC to give the title compound (382 mg, 47% yield)as a yellow solid. LC/MS (ESI, m/z): [M+1]⁺=358.1, 360.1.

3-[7-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(Intermediate XV)

Step 1—Tert-Butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-7-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

To a mixture of3-(7-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (461 mg, 1.29mmol, Intermediate XU), tert-butyl(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (941 mg, 3.87 mmol,Intermediate IT), and Cs₂CO₃ (2.1 g, 6.45 mmol) in DMF was added CuI (49mg, 0.258 mmol) and PdCl₂(PPh₃)₂ (181 mg, 0.258 mmol). The mixture wasdegrassed with N₂ and stirred at 80° C. for 1 h under microwavecondition. The reaction mixture was cooled to rt, poured into water,then extracted with EtOAc (3×20 mL). The combined organic layers waswashed with water (20 mL×2) and brine (2×30 mL), dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography eluting with EA/DCM=1:1 to the title compound (410mg, 68% yield) as yellow solid. LC/MS (ESI, m/z): [M−55+H]⁺=466.1.

Step 2—Tert-Butyl(2-(2-(3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-7-yl)propoxy)ethoxy)ethyl)carbamate

To a solution of tert-butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-7-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(400 mg, 0.77 mmol) in EtOAc (5 mL) was added 10% palladium on activatedcarbon (81 mg). The mixture was hydrogened at rt overnight. The reactionmixture was filtered, the filtrate was concentrated in vacuo. Theresidue was purified by P-TLC eluting with EA/DCM=1:2 firstly, then thecrude compound was purified by prep HPLC to give the title compound (132mg, 66% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s,1H), 8.49 (dd, J=7.63, 1.50 Hz, 1H), 8.38-8.35 (m, 1H), 8.11 (d, J=7.88Hz, 1H), 7.47 (br. s., 1H), 7.24 (dd, J=7.63, 4.88 Hz, 1H), 7.12-7.18(m, 1H), 6.77-6.74 (m, 1H), 6.01 (br. s., 1H), 3.47-3.55 (m, 4H),3.45-3.37 (m, 4H), 3.15-3.02 (m, 4H), 2.80 (t, J=7.69 Hz, 2H), 2.73-2.68(m, 1H), 2.13-2.07 (m, 1H), 1.94-1.88 (m, 2H), 1.36 (s, 9H); LC/MS (ESI,m/z): [M+1]⁺=525.3.

Step3—3-[7-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-7-yl]propoxy]ethoxy]ethyl]carbamate (95.0 mg, 181 umol) in DCM (3 mL) was added TFA(722 mg, 6.34 mmol). The reaction mixture was stirred at 25° C. for 1hr. On completion, the reaction mixture was concentrated in vacuo togive the title compound (95 mg, 95% yield, TFA) as light yellow oil.LC-MS (ESI⁺) m/z 425.2 (M+H)⁺.

2-[2-(Cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxylic Acid(Intermediate×)

To a mixture of2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (400 mg, 1.11 mmol, Intermediate OM) in DCM (10 mL) was added TFA(127 mg, 1.11 mmol). The reaction mixture was stirred at 25° C. for 2hours. On completion, the reaction mixture was concentrated in vacuo togive the title compound (397 mg, 95% yield, TFA salt) as brown oil.LC-MS (ESI⁺) m/z 260.1 (M+H)⁺.

3-(4-Bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (IntermediateXY)

Step 1—9H-pyrido[2,3-b]indole 1-oxide

To a stirred solution of 9H-pyrido[2,3-b]indole (10 g, 59.5 mmol) inAcOH (100 mL) was added 30% H₂O₂ (50 mL) dropwise. After the addition,the reaction mixture was heated to 110° C. and stirred for 6 h. Then thereaction mixture was cooled to rt and concentrated in vacuo. To theresidue was added sat. aq. K₂CO₃ to basify to pH=8. The mixture wasstirred at rt overnight and filtered. The solid was washed with waterand dried to afford the title compound (7.3 g, 67% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (s, 1H), 8.36-8.34 (m, 1H),8.25-8.14 (m, 2H), 7.58-7.50 (m, 2H), 7.35-7.18 (m, 2H). LC/MS (ESI,m/z): [M+1]⁺=185.1

Step 2—4-bromo-9H-pyrido[2,3-b]indole

To a solution of 9H-pyrido[2,3-b]indole 1-oxide (9.3 g, 50.5 mmol) inDMF (100 mL) was added phosphorusoxybromide (29.0 g, 101.1 mmol) at rt.The reaction mixture was stirred at rt overnight and filtered. The solidwas washed with water and dried to afford the title compound (9.0 g, 73%yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.28 (s, 1H), 8.61(d, J=8.0 Hz, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.59-7.52 (m, 2H), 7.43-7.33(m, 2H). LC/MS (ESI, m/z): [M+1]⁺=247.3, 249.3.

Step3—3-(4-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

To a solution of 4-bromo-9H-pyrido[2,3-b]indole (8.8 g, 35.6 mmol) and18-crown-6 (1.9 g, 7.13 mmol) in THF (100 mL) was added NaHMDS (26.7 mL,53.4 mmol, 2N in THF) dropwise at −30° C. under N₂ atmosphere. Afteraddition, the reaction mixture was stirred at −30° C. for 1 h. Then1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate(20.4 g in 30 mL THF, 53.4 mmol) was added to solution dropwise. Afteraddition, the reaction mixture was stirred at −30° C. for 2 h andquenched by sat. aq. NH₄Cl (100 mL), then extracted with EA (150 mL×2).The combined organic layers were washed with brine (100 mL×2), driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by column to give the title compound (10.0 g, 59% yield) asa white solid. LC/MS (ESI, m/z): [M+1]⁺=478.3.

Step 4—3-(4-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione

To a solution of3-(4-bromo-9H-pyrido[2,3-b]indol-9-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione(10 g, 20.9 mmol) in toluene (50 mL) was added methanesulfonic acid (20mL). The reaction solution was heated to 110° C. and stirred for 2 h.The reaction mixture was cooled to rt and concentrated to removetoluene. The residue was diluted with CH₃CN and purified via reversephase column chromatography (CH₃CN/H₂O=5%-80%) to give the titlecompound (3.7 g, 50% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.19 (s, 1H), 8.57 (d, J=7.9 Hz, 1H), 8.30 (d, J=5.3 Hz, 1H),7.73-7.69 (m, 1), 7.63 (t, J=7.9 Hz, 1), 7.56 (d, J=5.3 Hz, 1), 7.41 (t,J=7.9 Hz, 1H), 6.10 (s, 1H), 3.14-2.98 (m, 2H), 2.73-2.68 (m, 1H),2.18-2.12 (m, 1H). LC/MS (ESI, m/z): [M+1]⁺=358.0.

3-[4-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(Intermediate XZ)

Step 1—Tert-Butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate

To a mixture of3-(4-bromo-9H-pyrido[2,3-b]indol-9-yl)piperidine-2,6-dione (0.3 g, 0.84mmol, Intermediate XY), tert-butyl(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (0.31 g, 1.26 mmol,Intermediate IT), Cs₂CO₃ (2.7 g, 8.38 mmol) in DMF (10 mL) was added CuI(16 mg, 0.084 mmol) and PdCl₂(PPh₃)₂ (0.12 g, 0.17 mmol). The mixturewas degrassed with N₂ and stirred at 80° C. for 1 h under microwavecondition. The reaction mixture was cooled to rt, poured into water,then extracted with EtOAc (3×20 mL). The combined organic layers waswashed with water (20 mL×2) and brine, dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography eluting with EA/DCM=1:1 to give the title compound (0.16g, 37% yield) as yellow solid. LC/MS (ESI, m/z): [M−55+H]⁺=466.1.

Step 2—Tert-Butyl(2-(2-(3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-4-yl)propoxy)ethoxy)ethyl)carbamate

To a solution of tert-butyl(2-(2-((3-(9-(2,6-dioxopiperidin-3-yl)-9H-pyrido[2,3-b]indol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamate(0.16 g, 0.31 mmol) in EtOAc (5 mL) was added 10% palladium on activatedcarbon (32 mg). The mixture was hydrogened at rt overnight. Then thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by P-TLC eluting with EA/DCM=1:2firstly, then the crude compound was purified by prep HPLC to give thetitle compound (60 mg, 38% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.32 (d, J=5.1 Hz, 1H), 8.20 (d, J=7.9 Hz, 1), 8.12 (s, 1),7.53-7.46 (m, 1), 7.34-7.28 (m, 2H), 7.06-7.04 (m, 1H), 5.96 (s, 1H),5.00 (s, 1H), 3.66-3.56 (m, 8H), 3.41-3.24 (m, 4H), 3.09-2.99 (m, 3H),2.33-2.29 (m, 1H), 2.18-2.11 (m, 2H), 1.43 (s, 9H). LC/MS (ESI, m/z):[M+1]⁺=525.4.

Step3—3-[4-[3-[2-(2-Aminoethoxy)ethoxy]propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[2-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-4-yl]propoxy]ethoxy]ethyl]carbamate (66.0 mg, 125 umol) in DCM (2 mL) was added TFA(573 mg, 5.03 mmol). The mixture was stirred at 25° C. for 2 hrs. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (67.0 mg, 95% yield, TFA) as light yellow oil. LC-MS (ESI⁺) m/z425.0 (M+H)⁺.

Tert-Butyl 3-(prop-2-ynoxymethyl)azetidine-1-carboxylate (IntermediateYA)

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate(2.00 g, 10.7 mmol, CAS #142253-56-3) in DMF (20 mL) was added NaH (641mg, 16.0 mmol, 60% oil dispersion) at 0° C. Thirty minutes later,3-bromoprop-1-yne (1.40 g, 11.8 mmol, 1.01 mL, CAS #106-96-7) was addedand the reaction mixture was stirred at 25° C. for 12 hrs. Oncompletion, the mixture was quenched with water (50 mL), then extractedwith EA (2×30 mL). The combined organic layer was washed with brine (50mL), dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel chromatography (SiO₂,PE:EA=15:1) to give the title compound (0.60 g, 25% yield) as yellowoil. ¹H NMR (400 MHz, CDCl₃) δ 4.17 (d, J=2.4 Hz, 2H), 4.00 (t, J=8.4Hz, 2H), 3.71-3.64 (m, 4H), 2.87-2.69 (m, 1H), 2.45 (t, J=2.4 Hz, 1H),1.44 (s, 9H).

3-[4-[3-(Azetidin-3-ylmethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YB)

Step 1—Tert-Butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxymethyl]azetidine-1-carboxylate

To a solution of tert-butyl3-(prop-2-ynoxymethyl)azetidine-1-carboxylate (480 mg, 2.13 mmol,Intermediate YA) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HP) in DMF (8 mL) was added Pd(PPh₃)₂Cl₂(166 mg, 236 umol), Cs₂CO₃ (1.93 g, 5.91 mmol), and CuI (45.1 mg, 236umol) under N₂ atmosphere. The mixture was de-gassed and then heated at80° C. for 2 hrs under N₂ atmosphere. On completion, the mixture wasconcentrated in vacuo. The residue was washed with ethyl acetate (60mL), the filtrate was concentrated in vacuo. The residue was purified byreversed-phase HPLC (0.1% FA condition) to give the title compound (450mg, 63% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (m,1H), 7.20-7.10 (m, 2H), 7.06-6.99 (m, 1H), 5.39 (dd, J=5.6, 12.8 Hz,1H), 4.47 (s, 2H), 3.64 (s, 3H), 3.60-3.56 (m, 4H), 2.80-2.70 (m, 4H),2.61-2.59 (m, 2H), 2.06-1.98 (m, 1H), 1.35 (s, 9H); LC-MS (ESI⁺) m/z505.2 (M+Na)⁺.

Step 2—Tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxymethyl]azetidine-1-carboxylate

To a solution of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxymethyl]azetidine-1-carboxylate(400 mg, 829 umol) in THF (8 mL) was added Pd/C (80.0 mg, 10% wt) andPd(OH)₂/C (80.0 mg, 10% wt) under N₂ atmosphere. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred at 25° C. for 12 hrs. On completion, the mixture was filteredand then the filtrate was concentrated in vacuo to give the titlecompound (400 mg, 79% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 6.99-6.95 (m, 2H), 6.87-6.85 (m, 1H), 5.37 (dd, J=5.2,12.4 Hz, 1H), 3.56 (s, 3H), 3.52-3.46 (m, 4H), 3.33 (s, 3H), 3.00-2.92(m, 2H), 2.91-2.84 (m, 1H), 2.78-2.55 (m, 4H), 2.04-1.96 (m, 1H),1.89-1.77 (m, 2H), 1.38-1.36 (m, 9H). LC-MS (ESI⁺) m/z 509.3 (M+Na)⁺.

Step3—3-[4-[3-(Azetidin-3-ylmethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxymethyl]azetidine-1-carboxylate (313 mg, 514 umol) in DCM (3 mL)was added TFA (3 mL). The mixture was stirred at 25° C. for 2 hrs. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (230 mg, 89% yield, TFA salt) as yellow solid. LC-MS (ESI⁺) m/z387.2 (M+H)⁺.

Tert-Butyl N-but-3-ynyl-N-methyl-carbamate (Intermediate YC)

Step 1—Tert-butyl N-but-3-ynylcarbamate

To a solution of but-3-yn-1-amine (4.30 g, 40.7 mmol, HCl) and TEA (4.12g, 40.7 mmol) in DCM (150 mL) was added (Boc)₂O (9.16 g, 41.9 mmol)dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30minutes. Then TEA (4.12 g, 40.7 mmol) added dropwise at 0° C. Thereaction mixture was stirred at 25° C. for 1 hour. On completion, thereaction mixture was diluted with DCM (400 mL) and washed with water(2×100 mL) and HCl (0.5 N, 3×300 mL). The organic layers were dried withanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica column chromatography to give thetitle compound (4.00 g, 58% yield) as colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 4.93 (s, 1H), 3.25 (q, J=6.0 Hz, 2H), 2.35 (dt, J=2.7, 6.0 Hz,2H), 1.98 (t, J=2.7 Hz, 1H), 1.41 (s, 9H).

Step 2—Tert-Butyl N-but-3-ynyl-N-methyl-carbamate

To a solution of tert-butyl N-but-3-ynylcarbamate (1.00 g, 5.91 mmol) inTHF (20 mL) was added NaH (354 mg, 8.86 mmol, 60% oil dispersion) at 0°C. The reaction mixture was stirred at 0° C. for 0.5 hour, then MeI(1.26 g, 8.86 mmol) was added. The reaction mixture was stirred at 25°C. for 12 hours. On completion, the reaction mixture was quenched withsat. NH₄Cl (30 mL) and extracted with EA (2×100 mL). The combinedorganic layers were washed with brine (50 mL), dried with anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo. The residuewas purified by column chromatography to give the title compound (1.00g, 92% yield) as colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 3.43-3.28 (m,2H), 2.87 (s, 3H), 2.44-2.33 (m, 2H), 1.95 (t, J=2.4 Hz, 1H), 1.44 (s,9H).

3-[3-Methyl-4-[4-(methylamino)butyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YD)

Step 1—Tert-ButylN-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynyl]-N-methyl-carbamate

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP) and 4Å molecular sieves (50 mg) in DMF(5 mL) was added Pd(PPh₃)₂Cl₂ (103 mg, 147 umol), CuI (56.3 mg, 295umol) and Cs₂CO₃ (1.93 g, 5.91 mmol). The reaction mixture was degassedwith N₂ for three times. Then tert-butyl N-but-3-ynyl-N-methyl-carbamate(487 mg, 2.66 mmol, Intermediate YC) was added. The reaction mixture wasstirred at 85° C. for 2 hours. On completion, the reaction mixture wasfiltered. The organic layer was diluted with EA (300 mL), washed withsat.NH₄Cl (2×100 mL) and brine (100 mL), dried with anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by reverse phase flash (0.1%, FA) to give the title compound(400 mg, 61% yield) as a light yellow solid, LC-MS (ESI⁺) m/z 463.1(M+Na)⁺.

Step 2—Tert-ButylN-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]butyl]-N-methyl-carbamate

To a solution of tert-butylN-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]but-3-ynyl]-N-methyl-carbamate(400 mg, 908 umol) in THF (25 mL) was added Pd/C (200 mg, 10 wt %) andPd(OH)₂/C (1.28 g, 10 wt %). The reaction mixture was stirred at 25° C.under H₂ (15 psi) for 12 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo to give the title compound (400 mg,99% yield) as a white solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),6.99-6.93 (m, 2H), 6.89-6.84 (m, 1H), 5.40-5.32 (m, 1H), 3.55 (s, 3H),3.24-3.14 (m, 2H), 2.99-2.82 (m, 3H), 2.75 (s, 3H), 2.72-2.59 (m, 2H),2.04-1.94 (m, 1H), 1.63-1.48 (m, 4H), 1.36 (s, 9H).

Step3—3-[3-Methyl-4-[4-(methylamino)butyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]butyl]-N-methyl-carbamate(390 mg, 877 umol) in DCM (15 mL) was added HCl/dioxane (4 M, 15 mL).The reaction mixture was stirred at 25° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo to give the titlecompound (300 mg, 89% yield, HCl) as a white solid. LC-MS (ESI⁺) m/z345.2 (M+H)⁺.

2-[2-[Tert-butoxycarbonyl(methyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (Intermediate YE)

Step 1—4-Bromo-N-methyl-pyridin-2-amine

To a solution of 4-bromo-2-fluoro-pyridine (5.00 g, 28.4 mmol, CAS#128071-98-7) in THF (50.0 mL) was added a solution of MeNH₂ in EtOH(2.00 M, 42.6 mL). The mixture was stirred at 120° C. for 2 hrs underseal tube. The mixture was concentrated in vacuo. The mixture waspurified by silica gel column (PE:EA=80:1) to give the title compound(4.50 g, 84% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ7.87-7.84 (m, 1H), 6.75-6.74 (m, 1H), 6.66-6.65 (m, 1H), 6.64 (s, 1H),2.75 (s, 3H).

Step 2—Tert-butyl N-(4-bromo-2-pyridyl)-N-methyl-carbamate

To a solution of 4-bromo-N-methyl-pyridin-2-amine (4.00 g, 21.4 mmol) inTHF (30.0 mL) was added LiHMDS (1.00 M, 47.1 mL) dropwise at −5° C. Thena solution of (Boc)₂O (4.67 g, 21.4 mmol, 4.91 mL) in THF (10.0 mL) wasadded into the above mixture slowly. The reaction mixture was stirred at−5° C. for 10 minutes, then heated to 20° C. and stirred for 1 hr. Thereaction mixture was quenched with sat. NH₄Cl (100 ml), extracted withEA (2×50 mL), then concentrated in vacuo to give a residue. The residuewas purified by silica gel column chromatography (PE:EA=100:1-8:1) togive the title compound (5.00 g, 81% yield) as a yellow liquid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.16 (d, J=5.6 Hz, 1H), 8.02-8.01 (m, 1H), 7.13(dd, J=5.2 Hz, J=5.6 Hz, 1H), 3.39 (s, 3H), 1.53 (s, 9H).

Step 3—Ethyl2-[2-[tert-butoxycarbonyl(methyl]amino]-4-pyridyl)oxazole-4-carboxylate

A mixture of tert-butyl N-(4-bromo-2-pyridyl)-N-methyl-carbamate (4.00g, 13.9 mmol), ethyl oxazole-4-carboxylate (1.97 g, 13.9 mmol, CAS#170487-38-4), Pd(OAc)₂ (313 mg, 1.39 mmol), tris-o-tolylphosphane (848mg, 2.79 mmol) and K₂CO₃ (5.78 g, 41.8 mmol) in DMF (60.0 mL) wasdegassed and purged with N₂ three times, and then the mixture wasstirred at 70° C. for 16 hrs under N₂ atmosphere. On completion, thereaction mixture was diluted by addition H₂O (30 mL) and extracted withEA (3×50 mL). The combined organic layers were washed with saturatedNaCl (2×100 mL), dried over Na₂SO₄, filtered and concentrated in vacuoto give a residue. The crude product was purified by reverse phase (0.1%FA condition) to give the title compound (2.20 g, 45% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=6.8 Hz, 1H), 8.42 (s, 1H),8.33 (s, 1H), 7.71-7.69 (m, 1H), 4.47-4.41 (m, 2H), 3.45 (s, 3H), 1.56(s, 9H), 1.42 (t, J=13.2 Hz, 3H).

Step4—2-[2-[Tert-butoxycarbonyl(methyl)amino]-4-pyridyl]oxazole-4-carboxylicAcid

To a solution of ethyl2-[2-[tert-butoxycarbonyl(methyl)amino]-4-pyridyl]oxazole-4-carboxylate(200 mg, 575 umol) in THF (10.0 mL) and H₂O (2.00 mL) was added LiOH(68.9 mg, 2.88 mmol). The mixture was stirred at 20° C. for 15 hrs. Oncompletion, the reaction mixture was quenched with water (1 mL), and themixture was acidified with 1N HCl solution until the pH=5. The aqueousphase was extracted with EA (3×10 mL). The combined organic layer waswashed with brine (2×10 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (160 mg, 87% yield) asan off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.57 (d,J=5.2 Hz, 1H), 8.35 (s, 1H), 7.65 (dd, J=4.8 Hz, J=5.2 Hz, 1H), 3.37 (s,3H), 1.52 (s, 9H).

Tert-Butyl 3-prop-2-ynoxypyrrolidine-1-carboxylate (Intermediate YG)

To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate(5.00 g, 26.7 mmol, CAS #101469-92-5) in THF (150 mL) was added NaH(1.60 g, 40.0 mmol, 60% oil dispersion) at 0° C. The reaction mixturewas stirred at 0° C. for 30 minutes. Then TBAI (986 mg, 2.67 mmol) and3-bromoprop-1-yne (4.37 g, 29.3 mmol, CAS #106-96-7) was added. Thereaction mixture was stirred at 25° C. for 12 hours. On completion, thereaction mixture was diluted with EA (300 mL) and quenched with sat.NH₄Cl (100 mL). The organic layer was washed with water (2×30 mL) andbrine (50 mL). The organic layer was dried with anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica column chromatography to give the title compound(5.90 g, 98% yield) as light yellow oil, ¹H NMR (300 MHz, CDCl3) δ4.29-4.21 (m, 1H), 4.17-4.10 (m, 2H), 3.51-3.32 (m, 4H), 2.50-2.34 (s,1H), 2.02-1.90 (m, 2H), 1.43 (s, 9H).

3-[3-Methyl-2-oxo-4-[3-[(3S)-pyrrolidin-3-yl]oxypropyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YH)

Step 1—Tert-Butyl(3S)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]pyrrolidine-1-carboxylate

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg,1.77 mmol, Intermediate HP) in DMF (10 mL) was added Pd(PPh₃)₂Cl₂ (124mg, 177 umol), CuI (33.7 mg, 177 umol) and Cs₂CO₃ (2.31 g, 7.08 mmol).The reaction mixture was degassed with N₂ three times. Then tert-butyl3-prop-2-ynoxypyrrolidine-1-carboxylate (598 mg, 2.66 mmol, IntermediateYG) was added. The reaction mixture was stirred at 80° C. for 8 hours.On completion, the reaction mixture was filtered. The filtrate wasconcentrated in vacuo. The residue was purified by reversed-phase flash(FA, 0.1%) to give the title compound (450 mg, 52% yield) as a yellowsolid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1), 7.19-7.10 (m, 2H), 7.04(d, J=8.0 Hz, 1), 5.44-5.34 (m, 1), 4.48 (s, 2H), 4.32-4.25 (m, 1H),3.63 (s, 3H), 3.29-3.07 (m, 4H), 2.94-2.82 (m, 1H), 2.77-2.62 (m, 2H),2.56-2.52 (m, 1H), 2.04-1.92 (m, 3H), 1.38 (d, J=9.2 Hz, 9H).

Step 2—Tert-Butyl(3S)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]pyrrolidine-1-carboxylate

To a solution of tert-butyl(3S)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]pyrrolidine-1-carboxylate (400 mg, 828 umol) in THF (25 mL)was added Pd/C (200 mg, 10 wt %) and Pd(OH)₂/C (200 mg, 10 wt %). Thereaction mixture was stirred at 25° C. for 12 hours under H₂ (15 psi).On completion, the reaction mixture was filtered and concentrated invacuo to give the title compound (400 mg, 99% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 6.98-6.94 (m, 2H), 6.88-6.84(m, 1H), 5.39-5.31 (m, 1H), 4.05-4.00 (m, 1H), 3.55 (s, 3H), 3.47-3.39(m, 2H), 3.30-3.22 (m, 4H), 2.96-2.84 (m, 3H), 2.76-2.60 (m, 2H),2.55-2.52 (m, 2H), 2.02-1.96 (m, 1H), 1.93-1.87 (m, 2H), 1.84-1.78 (m,2H), 1.40 (s, 10H).

Step3—3-[3-Methyl-2-oxo-4-[3-[(3S)-pyrrolidin-3-yl]oxypropyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl(3S)-3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]pyrrolidine-1-carboxylate (395 mg, 811 umol) in DCM (15 mL) wasadded HCl/dioxane (4 M, 15 mL). The reaction mixture was stirred at 25°C. for 1 hour. On completion, the reaction mixture was concentrated invacuo to give the title compound (300 mg, 87% yield, HCl) as a whitesolid. LC-MS (ESI⁺) m/z 387.2 (M+H)⁺.

[3-Methyl-4-[[4-(methylaminomethyl)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YI)

Step 1—Tert-ButylN-[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]methyl]-N-methyl-carbamate

To a solution of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(150 mg, 522 umol, Intermediate WW) and tert-butylN-methyl-N-(4-piperidylmethyl)carbamate (119 mg, 522 umol, CAS#138022-04-5) in THF (2 mL) and DMF (0.5 mL) was added HOAc (31.4 mg,522 umol) at 25° C. The mixture was stirred for 0.5 hour, thenNaBH(OAc)₃ (221 mg, 1.04 mmol) was added. The mixture was stirred at 25°C. for 2 hours. On completion, the mixture was quenched by water (0.2mL), and concentrated in vacuo to give a residue. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(180 mg, 69% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (s,1H), 8.24 (s, 1H), 7.08-6.97 (m, 2H), 6.85-6.72 (m, 1H), 5.28-5.22 (m,1H), 3.78 (d, J=5.0 Hz, 5H), 3.68-3.51 (m, 2H), 3.10 (s, 2H), 3.04-2.94(m, 2H), 2.94-2.90 (m, 1H), 2.86 (s, 4H), 2.81-2.72 (m, 1H), 2.27-2.20(m, 1H), 1.71-1.62 (m, 2H), 1.46 (s, 9H), 1.39-1.21 (m, 2H); LC-MS(ESI⁺) m/z 500.4 (M+H)⁺.

Step2—[3-Methyl-4-[[4-(methylaminomethyl)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine2,6-dione

To a mixture of tert-butylN-[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidyl]methyl]-N-methyl-carbamate (106 mg, 212 umol) in DCM(2 mL) was added TFA (483 mg, 4.24 mmol) at 25° C. The mixture wasstirred at 25° C. for 2 hours. On completion, the reaction mixture wasconcentrated in vacuo give the title compound (108 mg, 99% yield, TFA).LC-MS (ESI⁺) m/z 399.9 (M+H)⁺.

3-[3-Methyl-4-[[(2S)-2-(methylaminomethyl)morpholin-4-yl]methyl]-2-oxo-benzimidazo1-1-yl]piperidine-2,6-dione (Intermediate YJ)

Step1—Tert-Butyl-N-[[(2R)-4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-[[(2R)-morpholin-2-yl]methyl]carbamate (158 mg, 689 umol,synthesized via Steps 1-5 of Intermediate WP),1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(180 mg, 626 umol, Intermediate WW) in DMF (3.00 mL) and THF (10.0 mL)was added HOAc (75.2 mg, 1.25 mmol). The mixture was stirred at 20° C.for 0.5 hr, then NaBH(OAc)₃ (265 mg, 1.25 mmol) was added, and themixture was stirred at 20° C. for 14 hrs. On completion, the reactionmixture was quenched with H₂O (3 mL) at 20° C., and extracted with EA 60mL (3×20 mL). The combined organic layers were washed with brine (2×10mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by reversed-phase HPLC (0.1% FAcondition) to give the title compound (215 mg, 68% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 6.88-6.86 (m, 11H),6.82-6.80 (m, 1H), 6.69 (d, J=7.6 Hz, 1H), 5.19-5.07 (m, 1H), 3.79-3.72(m, 1H), 3.72-3.71 (m, 3H), 3.57 (s, 2H), 3.53-3.47 (m, 2H), 3.39-3.36(m, 2H), 2.87 (s, 2H), 2.83 (s, 3H), 2.73-2.72 (m, 1H), 2.63-2.54 (m,2H), 2.19-2.12 (m, 2H), 1.87-1.80 (m, 1H), 1.36 (s, 9H).

Step2—3-[3-Methyl-4-[[(2S)-2-(methylaminomethyl)morpholin-4-yl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[[(2R)-4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl] methyl]morpholin-2-yl] methyl]-N-methyl-carbamate (100 mg, 199 umol) in DCM(3.00 mL) was added HCl/dioxane (4.00 M, 5.00 mL). The mixture wasstirred at 20° C. for 1 hr. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (87.0 mg, quant. crudeyield, HCl) as yellow solid. LC-MS (ESI⁺) m/z 401.2 (M+H)⁺.

3-[3-Methyl-4-[[(2R)-2-(methylaminomethyl)morpholin-4-yl]]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YK)

Step1—N-[[(2S)-4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde(249 mg, 868 umol, Intermediate WW) and tert-butylN-methyl-N-[[(2S)-morpholin-2-yl]methyl]carbamate (200 mg, 868 umol,Intermediate YM) in THF (15 mL) was added TEA (87.8 mg, 868 umol). Thereaction mixture was stirred at 25° C. for 15 minutes. Then AcOH (156mg, 2.61 mmol) and NaBH(OAc)₃ (552 mg, 2.61 mmol) was added. Thereaction mixture was stirred at 25° C. for 12 hours. On completion, thereaction was quenched with water (3 mL) and the reaction mixture wasconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA) to give the title compound (250 mg, 57% yield) as a white solid.LC-MS (ESI⁺) m/z 502.1 (M+H)⁺.

Step2—3-[3-Methyl-4-[[(2R)-2-(methylaminomethyl)morpholin-4-yl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2S)-4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]morpholin-2-yl]methyl]-N-methyl-carbamate (100 mg, 199 umol) inDCM (1 mL) was added HCl/dioxane (4 M, 20.0 mL). The reaction mixturewas stirred at 25° C. for 30 minutes. On completely, the reactionmixture was concentrated in vacuo to give the title compound (80.0 mg,910% yield, HCl) as a white solid. LC-MS (ESI⁺) m/z 402.1 (M+H)⁺.

3-[3-Methyl-2-oxo-4-[2-(4-piperidyl)ethynyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YL)

Step 1—Tert-Butyl4-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]ethynyl]piperidine-1-carboxylate

To a solution of3-(4-bromo-3-methyl-2-oxobenzimidazol-1-yl)piperidine-2,6-dione (400 mg,1.18 mmol, Intermediate HP), and tert-butyl4-ethynylpiperidine-1-carboxylate (446 mg, 2.13 mmol, CAS #287192-97-6)in DMF (5.00 mL) was added Cs₂CO₃ (1.93 g, 5.91 mmol), 4Å molecularsieves (100 mg), Pd(PPh₃)₂Cl₂ (83.0 mg, 118 umol) and CuI (22.5 mg, 118umol). The mixture was stirred at 80° C. for 2 hrs under N₂. Oncompletion, the reaction mixture was filtered and the filter cake waswashed with ACN (10 mL). The filtrate was concentrated in vacuo to givea residue. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (330 mg, 707 umol, 60% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.13-7.11 (m, 1H),7.07-7.05 (m, 1H), 7.01-6.97 (m, 1H), 5.40-5.36 (m, 1H), 3.72-3.66 (m,2H), 3.63 (s, 3H), 3.12-3.07 (m, 2H), 2.93-2.87 (m, 2H), 2.75-2.68 (m,1H), 2.65-2.60 (m, 1H), 2.04-1.99 (m, 1H), 1.88-1.85 (m, 2H), 1.8-1.50(m, 2H), 1.40 (s, 9H).

Step2—3-[3-Methyl-2-oxo-4-[2-(4-piperidyl)ethynyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]ethynyl]piperidine-1-carboxylate (300 mg, 643 umol) in DCM (3.00 mL) was addedZnBr₂ (2.17 g, 9.65 mmol). The mixture was stirred at 20° C. for 20 hrs.On completion, the reaction mixture was concentrated in vacuo to givethe title compound (235 mg, 99% yield) as yellow gum. LC-MS (ESI⁺) m/z367.2 (M+H)⁺.

Tert-butyl N-methyl-N-[[(2S)-morpholin-2-yl]methyl]carbamate(Intermediate YM)

Step 1—Benzyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate

To a solution of [(2S)-morpholin-2-yl]methanol (5 g, 32.5 mmol, HCl; CAS#132073-83-7) and NaHCO₃ (6.84 g, 81.4 mmol) in a mixed solvent of ACN(10 mL) and H₂O (10 mL) was added CbzCl (8.33 g, 48.8 mmol). Thereaction mixture was stirred at 25° C. for 12 hrs. On completion, themixture was concentrated in vacuo to remove ACN. The residue wasextracted with EA (2×20 mL), then the combined organic layers wereconcentrated in vacuo. The residue was purified by silica gel column(PE:EA=1:1) to give the title compound (7.1 g, 87% yield) as colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.33 (m, 5H), 5.17 (d, J=2.0 Hz,2H), 4.08-3.88 (m, 3H), 3.77-3.65 (m, 1H), 3.63-3.46 (m, 3H), 3.13-2.73(m, 2H), 2.07-1.96 (m, 1H). LC-MS (ESI⁺) m/z 274.1 (M+Na)⁺.

Step 2—Benzyl (2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate

To a solution of benzyl (2S)-2-(hydroxymethyl)morpholine-4-carboxylate(7.1 g, 28.2 mmol) and triethylamine (5.72 g, 56.5 mmol) indichloromethane (70 mL) was added methanesulfonyl chloride (4.86 g, 42.3mmol) at 0° C. The reaction mixture was stirred at 25° C. for 1 hr. Oncompletion, the mixture was diluted with dichloromethane (20 mL) andwashed with water (3×30 mL). The organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the titlecompound (9.31 g, 100% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ7.43-7.33 (m, 5H), 5.20-5.15 (m, 2H), 4.26 (d, J=4.8 Hz, 2H), 4.10-3.83(m, 3H), 3.80-3.65 (m, 1H), 3.63-3.48 (m, 1H), 3.08 (s, 3H), 3.07-2.75(m, 2H).

Step 3—Benzyl (2R)-2-(methylaminomethyl)morpholine-4-carboxylate

A solution of benzyl(2S)-2-(methylsulfonyloxymethyl)morpholine-4-carboxylate (9.31 g, 28.2mmol) in EtOH (10 mL) saturated with methanamine (58.5 g, 565 mmol) wasstirred under 50 Psi at 80° C. for 12 hrs in a 100 mL of autoclave. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (7.47 g, 100% yield) as yellow oil, which was used for the nextstep without purification.

Step 4—Benzyl(2R)-2-[[tert-butoxycarbonyl(methyl)amino]methyl]morpholine-4-carboxylate

To a solution of benzyl(2R)-2-(methylaminomethyl)morpholine-4-carboxylate (7.47 g, 28.2 mmol)in MeOH (100 mL) was added (Boc)₂O (9.25 g, 42.4 mmol, 9.74 mL) and TEA(4.29 g, 42.4mmol). The reaction mixture was stirred at 25° C. for 12hrs. On completion, the mixture was concentrated in vacuo. The residuewas purified by silica gel column (PE:EA=5:1) to give the title compound(9.10 g, 88% yield) as yellow oil, ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.30(m, 5H), 5.24-5.09 (m, 2H), 4.11-3.83 (m, 3H), 3.68-3.34 (m, 3H),3.30-3.14 (m, 1H), 3.09-2.97 (m, 1H), 2.94 (s, 3H), 2.80-2.62 (m, 1H),1.47 (s, 9H).

Step 5—Tert-butyl N-methyl-N-[[(2S)-morpholin-2-yl]methyl]carbamate

To a solution of benzyl(2R)-2-[[tert-butoxycarbonyl(methyl)amino]methyl]morpholine-4-carboxylate(9.1 g, 24.9 mmol) in THF (100 mL) was added Pd/C (1.00 g, 10% wt) underN₂ atmosphere. The suspension was degassed and purged with H₂ threetimes. The mixture was stirred under H₂ (15 Psi) at 25° C. for 12 hrs.On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (5.7 g, 99% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.91-3.83 (m, 1H), 3.68-3.55(m, 2H), 3.48-3.33 (m, 1H), 3.12 (dd, J=6.2, 14.4 Hz, 1H), 2.94 (s, 3H),2.92-2.88 (m, 1H), 2.86 (dd, J=3.2, 10.8 Hz, 1H), 2.84-2.78 (m, 1H),2.57 (dd, J=10.3, 12.0 Hz, 1H), 1.47 (s, 9H).

3-[4-(Aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YN)

Step1—1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbonitrile

To a solution of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HP) in DMF (10 mL) was added Zn (CN)₂ (190mg, 1.62 mmol) and Pd(PPh₃)₄ (180 mg, 155 umol) at 25° C. The mixturewas stirred at 100° C. for 3 hours under N₂. On completion, the mixturewas cooled to 25° C. The mixture was filtered, and the cake was washedwith EA (30 mL). The filtrate and washing were combined and concentratedin vacuo. The residue was purified by reversed phase flash (FAcondition) to give the title compound (100 mg, 24% yield) as lightyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H), 7.48 (d, J=7.6Hz, 2H), 7.19 (t, J=8.0 Hz, 1H), 5.47-5.44 (m 1H), 3.61 (s, 3H),2.72-2.69 (m, 1H), 2.66-2.62 (m, 2H), 2.07-2.03 (m, 1H); LC-MS (ESI⁺)m/z 285.1 (M+H)⁺.

Step 2—Tert-ButylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]carbamate

To a solution of 1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-4-carbonitrile (100mg, 351 umol) and Boc₂O (85.0 mg, 389 umol) in THF (2 mL) and DMF (2 mL)was added Raney-Ni (100 mg) at 20° C. The mixture was stirred at 30° C.for 16 hours under H₂ (50 Psi). On completion, the mixture was filtered,and the filter cake was washed with THF (20 mL). The filtrate andwashing were combined and concentrated in vacuo to give the titlecompound (120 mg, 87% yield) as light yellow gum. LC-MS (ESI⁺) m/z 411.2(M+Na)⁺.

Step3—3-[4-(Aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl] methyl]carbamate(120 mg, 308 umol) in DCM (2 mL) was added TFA (1 mL) at 20° C. Themixture was stirred at 20° C. for 1 hour. On completion, the mixture wasconcentrated in vacuo to give the title compound (120 mg, 96% yield,TFA) as light yellow solid. LC-MS (ESI⁺) m/z 311.2 (M+Na)⁺.

Tert-Butyl N-methyl-N-(3-prop-2-ynoxycyclobutyl)carbamate (IntermediateYO)

Step 1—3-(Methylamino)cyclobutanol

To a stirred solution of LAH (2.43 g, 64.1 mmol) in THF (100 mL) wasadded a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (10.0 g,53.4 mmol, CAS #389890-42-0) in THF (100 mL) at 0° C. Then the reactionmixture was stirred at 60° C. for 24 hrs. On completion, the reactionmixture was concentrated in vacuo. On completion, the mixture was cooledto 0° C., quenched with H₂O (2.4 mL) and added 15% NaOH (2.4 mL). Afterstirred for 15 minutes, H₂O (2.4 mL×3) was added into the above mixture.Then the mixture was warmed to rt and added anhydrous Na₂SO₄. Themixture was stirred for 10 minutes, filtered and the filtrate wasconcentrated in vacuo to give the title compound (4.90 g, 91% yield) ascolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 5.01 (s, 1H), 4.23-4.20 (m,1H), 3.13-3.00 (m, 1H), 2.13 (s, 3H), 1.93-1.84 (m, 4H), 1.70-1.47 (m,1H).

Step 2—Tert-Butyl N-(3-hydroxycyclobutyl)-N-methyl-carbamate

To a solution of 3-(methylamino)cyclobutanol (4.90 g, 48.4 mmol) inmethyl alcohol (50 mL) was added (Boc)₂O (11.6 g, 53.3 mmol, 12.2 mL)for 3 hr at 25° C. Then another batch of (Boc)₂0 (10.6 g, 48.4 mmol) wasadded. The mixture was stirred at 25° C. for another 19 hrs. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=1:1) to give the title compound (2.85 g, 30% yield) as yellowoil. ¹H NMR (DMSO-d₆) δ 4.94 (s, 1H), 4.25-4.21 (m, 1H), 4.10-4.19 (m,1H), 2.72 (s, 3H), 2.23-2.35 (m, 2H), 1.91-2.03 (m, 2H), 1.38 (s, 9H).

Step 3—Tert-Butyl N-methyl-N-(3-prop-2-ynoxycyclobutyl)carbamate

To a solution of tert-butyl N-(3-hydroxycyclobutyl)-N-methyl-carbamate(450 mg, 2.24 mmol) in THF (15 mL) was added NaH (107 mg, 2.68 mmol, 60%dispersion in oil), TBAI (82.6 mg, 223 umol) at 0° C., and the mixturewas stirred for 30 minutes. Then 3-bromoprop-1-yne (3.35 mmol, 289 uL)was added to the mixture at 0° C. The reaction mixture was stirred at10° C. for 18 hrs. On completion, the reaction mixture was quenched 30mL sat.aq NH₄Cl at 10° C. and diluted with 30 mL water. Then thereaction mixture was then extracted with EA (3×50 mL). The combinedorganic layers were washed with 50 mL brine, dried over Na₂SO₄, filteredand the filtrate was concentrated in vacuo to give the title compound(500 mg, 93% yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.68 (s,1H), 4.27-4.19 (m, 1H), 4.08 (d, J=2.4 Hz, 2H), 2.83 (s, 3H), 2.41 (t,J=2.4 Hz, 1H), 2.38-2.26 (m, 4H), 1.46 (s, 9H).

3-[3-methyl-4-[3-[3-(methylamino)cyclobutoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YP)

Step 1—Tert-ButylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]cyclobutyl]-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-(3-prop-2-ynoxycyclobutyl)carbamate (500 mg, 2.09 mmol,Intermediate YO) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (353mg, 1.04 mmol, Intermediate HP) in DMF (15 mL) was added CuI (39.8 mg,209 umol), Cs₂CO₃ (1.70 g, 5.22 mmol), Pd(PPh₃)Cl₂ (153 mg, 209 umol)and 4Å molecular sieves (600 mg) at 25° C. The reaction mixture wasstirred at 80° C. for 2 hrs. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was diluted with 30 mL water, and then extracted with EA(3×30 mL). The combined organic layers were washed with brine (30 mL),and then dried over Na₂SO₄, filtered and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (380 mg, 73% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1), 7.17 (d, J=7.6Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.06-7.00 (m, 1), 5.39 (dd, J=5.2, 12.8Hz, 1), 4.39 (s, 2H), 4.22 (t, J=6.8 Hz, 1), 3.63 (s, 3H), 3.29 (s, 1H),2.95-2.83 (m, 1H), 2.75 (s, 3H), 2.65-2.64 (m, 1H), 2.70-2.64 (m, 1H),2.36-2.30 (m, 2H), 2.26-2.16 (m, 2H), 2.09-1.98 (m, 1H), 1.38 (s, 9H);LC-MS (ESI⁺) m/z 397.0 (M+H−100)⁺.

Step 2—Tert-ButylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]cyclobutyl]-N-methyl-carbamate

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]cyclobutyl]-N-methyl-carbamate(340 mg, 685 umol) in THF (15 mL) was added Pd(OH)₂/C (400 mg, 685 umol,10 wt %) and Pd/C (400 mg, 685 umol, 20 wt %) at 25° C. The reactionmixture was stirred at 25° C. for 2 hrs under H₂ (15 psi). Oncompletion, the reaction mixture was filtered with celite and thefiltrate was concentrated in vacuo to give the title compound (330 mg,96% yield) as black oil. LC-MS (ESI⁺) m/z 501.2 (M+H)⁺.

Step3—3-[3-methyl-4-[3-[3-(methylamino)cyclobutoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]cyclobutyl]-N-methyl-carbamate (300 mg, 599 umol) in DCM (8 mL)was added HCl/dioxane (4 M, 5 mL) at 25° C. The reaction mixture wasstirred at 25° C. for 1 hr. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. The residue was purified byreverse phase (0.1% FA condition) to give the title compound (220 mg,910% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H),9.06 (s, 1H), 6.98-6.96 (m, 1H), 6.90-6.87 (m, 1H), 5.37 (dd, J=5.2,12.8 Hz, 1H), 4.23-4.14 (m, 1H), 3.57 (s, 3H), 3.35 (s, 3H), 3.00-2.92(m, 3H), 2.91-2.84 (m, 1H), 2.75-2.70 (m, 1H), 2.60 (s, 2H), 2.45 (t,J=5.6 Hz, 4H), 2.27-2.17 (m, 2H), 2.03-1.95 (m, 1H), 1.88-1.77 (m, 2H);LC-MS (ESI⁺) m/z 401.3 (M+H)⁺.

3-[3-Methyl-4-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YO)

Step 1—Tert-ButylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-[[(2R)-4-prop-2-ynylmorpholin-2-yl]methyl]carbamate (400 mg,1.49 mmol, Intermediate WP) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (336mg, 994 umol, Intermediate HP) in DMF (15 mL) was added Cs₂CO₃ (1.62 g,4.97 mmol), 4Å molecular sieves (500 mg, 994 umol), CuI (37.8 mg, 199umol) and Pd(PPh₃)₂Cl₂ (139 mg, 199 umol) at 25° C. The reaction mixturewas stirred at 80° C. for 2 hrs. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was diluted with water 30 mL, and then extracted with EA(3×20 mL). The combined organic layers were washed with brine (20 mL),and then dried over Na₂SO₄, filtered and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (340 mg, 65% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 11H), 7.18-7.13 (m,1H), 7.12-7.06 (m, 1H), 7.04-6.99 (m, 1H), 5.39 (dd, J=5.2, 12.4 Hz,1H), 3.83 (d, J=9.6 Hz, 1H), 3.64 (s, 3H), 3.62-3.46 (m, 4H), 3.34 (s,3H), 3.15 (s, 1H), 2.86-2.78 (m, 4H), 2.75-2.66 (m, 3H), 2.11-1.98 (m,2H), 1.35 (s, 9H); LC-MS (ESI⁺) m/z 526.3 (M+H)⁺.

Step 2—Tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]methyl]-N-methyl-carbamate (300 mg, 571 umol)in THF (20 mL) and Pd/C (200 mg, 20 wt %) was added Pd(OH)₂/C (200 mg,10 wt %) at 25° C. The reaction mixture was stirred at 25° C. for 2 hrsunder H₂ (15 psi). On completion, the reaction mixture was filtered withcelite and the filtrate was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (130 mg, 43% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 6.99-6.91 (m, 2H), 6.89-6.83 (m, 1H), 5.36(dd, J=5.2, 12.4 Hz, 1H), 3.77 (d, J=11.2 Hz, 1H), 3.55 (s, 3H), 3.46(t, J=10.4 Hz, 2H), 3.22 (d, J=5.2 Hz, 1H), 3.18-3.15 (m, 1H), 2.94-2.88(m, 2H), 2.84-2.76 (m, 3H), 2.72-2.62 (m, 4H), 2.52 (s, 3H), 2.39-2.34(m, 1H), 2.05-1.95 (m, 2H), 1.77-1.71 (m, 2H), 1.37 (s, 9H); LC-MS(ESI⁺) m/z 530.4 (M+H)⁺.

Step3—3-[3-Methyl-4-[3-[(2S)-2-(methylaminomethyl)morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]methyl]-N-methyl-carbamate (110 mg, 208 umol) inDCM (6 mL) was added HCl/dioxane (4 M, 3 mL) at 25° C. The reactionmixture was stirred at 25° C. for 1 hr. On completion, the reactionmixture was concentrated in vacuo to give the title compound (80.0 mg,89% yield) as a white solid. LC-MS (ESI⁺) m/z 430.2 (M+H)⁺.

3-[3-Methyl-4-[3-[(2S)-2-[2-(methylamino)ethyl]morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YR)

Step 1—BenzylN-[2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]ethyl]-N-methyl-carbamate

To a solution of benzylN-methyl-N-[2-[(2S)-4-prop-2-ynylmorpholin-2-yl]ethyl]carbamate (426 mg,1.35 mmol, Intermediate TX) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (350mg, 1.04 mmol, Intermediate HP) in DMF (15 mL) was added Cs₂CO₃ (1.69 g,5.18 mmol), CuI (39.4 mg, 207 umol), 4Å molecular sieves (500 mg, 147.86umol) and Pd(dppf)Cl₂ (151 mg, 207 umol) at 25° C. The reaction mixturewas stirred at 80° C. for 2 hrs. On completion, the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give the residue.The residue was diluted with water 30 mL, and then extracted with EA(3×20 mL). The combined organic layers were washed with brine (20 mL),and then dried over Na₂SO₄, filtered and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (400 mg, 67% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.34 (d, J=2.0Hz, 5H), 7.18-7.08 (m, 2H), 7.05-6.98 (m, 1H), 5.39 (dd, J=5.2, 12.8 Hz,1H), 5.05 (s, 2H), 3.84-3.74 (m, 1H), 3.63 (s, 3H), 3.56 (s, 3H),3.46-3.41 (m, 2H), 2.94-2.87 (m, 1H), 2.88-2.80 (m, 4H), 2.77-2.70 (m,2H), 2.67-2.58 (m, 2H), 2.31-2.25 (m, 1H), 2.08-1.98 (m, 2H), 1.65-1.55(m, 2H); LC-MS (ESI⁺) m/z 574.1 (M+H)⁺.

Step2—3-[3-Methyl-4-[3-[(2S)-2-[2-(methylamino)ethyl]morpholin-4-yl]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of benzylN-[2-[(2S)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]ethyl]-N-methyl-carbamate (370 mg, 645 umol)in THF (15 mL) was added Pd/C (300 mg, 20 wt %) and Pd(OH)₂/C (300 mg,10 wt %) at 25° C. The mixture was stirred at 25° C. for 2.5 hrs underH₂ (15 psi). On completion, the reaction mixture was filtered withcelite and the filtrate was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase (0.1% FA condition) to give thetitle compound (140 mg, 48% yield) as a brown solid. LC-MS (ESI⁺) m/z444.3 (M+H)⁺.

Tert-Butyl 4-(prop-2-ynoxymethyl)piperidine-1-carboxylate (IntermediateYS)

To a mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate(5.00 g, 23.2 mmol, CAS #123855-51-6) was added NaH (1.11 g, 27.8 mmol,60% oil dispersion) at 0° C. for 0.5 hour. Then 3-bromoprop-1-yne (4.14g, 27.8 mmol, 3.00 mL, CAS #106-96-7) and TBAI (857 mg, 2.32 mmol) wasadded to the mixture. The reaction mixture was stirred at 25° C. for 12hours. On completion, the reaction mixture was quenched by addition sat.H₂O (10 mL), and extracted with EA (50 mL×2). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated in vacuo togive the title compound (5.00 g, 84% yield) as yellow oil. ¹H NMR (400MHz, CDCl₃) δ 4.12 (d, J=2.4 Hz, 2H), 3.36 (d, J=6.2 Hz, 2H), 2.69 (t,J=12.2 Hz, 2H), 2.41 (t, J=2.4 Hz, 1H), 1.81-1.74 (m, 1H), 1.73-1.67 (m,2H), 1.45 (s, 9H), 1.15-1.10 (m, 2H).

3-[3-Methyl-2-oxo-5-[3-(4-piperidylmethoxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YT)

Step 1—Tert-Butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxymethyl]piperidine-1-carboxylate

To a mixture of tert-butyl4-(prop-2-ynoxymethyl)piperidine-1-carboxylate (749 mg, 2.96 mmol,Intermediate YS) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HN) in DMF (1 mL) was added Pd(PPh₃)₂Cl₂(83.0 mg, 118 umol), CuI (22.5 mg, 118 umol), Cs₂CO₃ (1.93 g, 5.91 mmol)and 4Å molecular sieves (10.0 mg, 147 umol). The reaction mixture wasstirred at 80° C. for 2 hours. On completion, the reaction mixture wasfiltered and concentrated in vacuo. The residue was purified by reversephase (0.1% FA condition) to give the title compound (320 mg, 52% yield)as a yellowish solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.19-11.03 (m, 1H),7.66-7.52 (m, 1), 7.32 (d, J=0.8 Hz, 1), 7.16-7.13 (m, 1), 5.39 (dd,J=12.8 Hz, 1H), 4.36 (s, 2H), 3.40 (t, J=2.4 Hz, 1H), 3.37 (d, J=6.2 Hz,2H), 3.34 (s, 3H), 3.30-3.27 (m, 2H), 2.97-2.82 (m, 1H), 2.76-2.64 (m,4H), 2.11-1.96 (m, 1H), 1.64 (s, 2H), 1.38 (s, 9H), 1.07-1.01 (m, 2H).

Step 2—Tert-Butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxymethyl]piperidine-1-carboxylate

To a mixture of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxymethyl]piperidine-1-carboxylate(320 mg, 626 umol) in THF (5 mL) was added Pd/C (100 mg, 626 umol, 10%wt) and Pd(OH)₂/C (100 mg, 626 umol, 10% wt). The mixture was stirred at25° C. for 12 hours under H₂ (15 psi). On completion, the mixture wasfiltered and concentrated in vacuo to give the title compound (320 mg,99 yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),7.69-7.50 (m, 1), 7.03-7.00 (m, 1), 6.87-6.84 (m, 1H), 5.33 (dd, J=12.8Hz, 1H), 3.92 (d, J=12.0 Hz, 2H), 3.38-3.34 (m, 3H), 3.31-3.27 (m, 2H),3.20 (t, J=6.6 Hz, 4H), 1.86-1.76 (m, 2H), 1.73-1.67 (m, 1H), 1.64-1.60(m, 2H), 1.55-1.44 (m, 2H), 1.38 (s, 9H), 1.35 (s, 2H).

Step3—3-[3-Methyl-2-oxo-5-[3-(4-piperidylmethoxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxymethyl]piperidine-1-carboxylate (310 mg, 602 umol) in DCM (5 mL)was added HCl/dioxane (4 M, 4.00 mL). The reaction mixture was stirredat 25° C. for 2 hours. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (220 mg, 88% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.07-6.97 (m,2H), 6.89-6.82 (m, 1H), 5.34 (dd, J=12.8 Hz, 1H), 3.57 (s, 4H),3.40-3.37 (m, 2H), 3.22-3.21 (m, 2H), 2.96-2.70 (m, 6H), 2.67-2.64 (m,2H), 1.85-1.81 (m, 2H), 1.52-1.47 (m, 1H), 1.41-1.33 (m, 4H), 0.90-0.81(m, 1H), 0.86 (t, J=7.2 Hz, 1H).

3-[3-Methyl-2-oxo-4-[3-(4-piperidylmethoxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YU)

Step 1—Tert-Butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxymethyl]piperidine-1-carboxylate

To a mixture of tert-butyl4-(prop-2-ynoxymethyl)piperidine-1-carboxylate (749 mg, 2.96 mmol,Intermediate YS) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HP) in DMF (5 mL) was added CuI (22.5 mg,118 umol), Cs₂CO₃ (1.93 g, 5.91 mmol), Pd(PPh₃)₂Cl₂ (83.0 mg, 118 umol)and 4Å molecular sieves (20.0 mg). The reaction mixture was stirred at80° C. for 4 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (300 mg, 49% yield) as brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.20-7.09 (m, 2H),7.06-7.00 (m, 1H), 5.43-5.36 (m, 1H), 4.43 (s, 2H), 4.10 (d, J=2.4 Hz,1H), 3.93 (d, J=10.8 Hz, 2H), 3.64 (s, 3H), 3.40-3.38 (m, 2H), 3.28 (d,J=6.4 Hz, 1H), 2.95-2.83 (m, 1H), 2.70-2.65 (m, 2H), 2.06-1.99 (m, 1H),1.81-1.70 (m, 1H), 1.67-1.60 (m, 2H), 1.38 (s, 9H), 1.08-1.01 (m, 2H).

Step 2—Tert-Butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxymethyl]piperidine-1-carboxylate

To a mixture of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxymethyl]piperidine-1-carboxylate(300 mg, 587 umol) in THF (30 mL) was added Pd/C (100 mg, 10 wt %) andPd(OH)₂/C (100 mg, 10 wt %). The reaction mixture was stirred at 25° C.for 12 hours under H₂ (15 psi) atmosphere. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (302 mg, 99% yield) as light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.08 (s, 1H), 6.96 (d, J=4.4 Hz, 2H), 6.88-6.83 (m, 1H),5.41-5.30 (m, 1H), 3.96-3.91 (m, 2H), 3.55 (s, 3H), 3.42 (t, J=5.6 Hz,2H), 3.28-3.18 (m, 4H), 2.99-2.92 (m, 2H), 2.90-2.83 (m, 1H), 2.71-2.66(m, 2H), 2.05-1.94 (m, 1H), 1.86-1.78 (m, 2H), 1.66-1.62 (m, 2H),1.51-1.46 (m, 1H), 1.39 (s, 9H), 1.06-0.99 (m, 2H).

Step3—3-[3-Methyl-2-oxo-4-[3-(4-piperidylmethoxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxymethyl]piperidine-1-carboxylate (290 mg, 563 umol) in DCM (2 mL)was added HCl/dioxane (4 M, 29.00 mL). The reaction mixture was stirredat 25° C. for 2 hours. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (254 mg, 99% yield, HClsalt) as white solid. LC-MS (ESI⁺) m/z 415.3 (M+H)⁺.

Tert-Butyl 3-prop-2-ynoxyazetidine-1-carboxylate (Intermediate YV)

To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g,28.8 mmol, CAS #141699-55-0) in THF (5 mL) was added NaH (1.39 g, 34.6mmol, 60% oil dispersion) at 0° C. for 0.5 hour. Then 3-bromoprop-1-yne(5.15 g, 34.6 mmol, 3.73 mL) and TBAI (1.07 g, 2.89 mmol) were added tothe mixture. The reaction mixture was stirred at 25° C. for 2 hours. Oncompletion, the reaction mixture was quenched with sat. NH₄Cl (50 mL),diluted with water (100 mL) and extracted with EA (2×100 mL). Thecombined organic layers was dried over Na₂SO₄, filtered and concentratedin vacuo to give a residue. The residue was purified by columnchromatography to give the title compound (5.70, 93% yield) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 4.45-4.37 (m, 1H), 4.13 (d, J=2.4 Hz,2H), 4.12-4.07 (m, 2H), 3.89 (dd, J=9.6 Hz, 2H), 2.45-2.43 (m, 1), 1.43(s, 9H).

3-[5-[3-(Azetidin-3-yloxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YW)

Step 1—Tert-Butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]azetidine-1-carboxylate

To a mixture of tert-butyl 3-prop-2-ynoxyazetidine-1-carboxylate (499mg, 2.37 mmol, Intermediate YV) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HN) in DMF (20 mL) was added Cs₂CO₃ (1.93 g,5.91 mmol), CuI (22.5 mg, 118 umol), Pd(PPh₃)₂Cl₂ (83.0 mg, 118 umol)and 4Å molecular sieves (100 mg). The reaction mixture was stirred at80° C. for 2 hours. On completion, the mixture was filtered andconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (300 mg, 54% yield) ascolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.66-7.59 (m,1H), 7.58-7.49 (m, 1H), 7.18-7.13 (m, 1), 4.49-4.43 (m, 1), 4.10-3.97(m, 4H), 3.77-3.76 (m, 1H), 3.77-3.72 (m, 1H), 3.46 (t, J=2.4 Hz, 1H),3.34 (s, 3H), 2.97-2.83 (m, 1H), 2.77-2.58 (m, 2H), 2.09-1.94 (m, 1H),1.37 (s, 9H).

Step 2—Tert-Butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]azetidine-1-carboxylate

To a solution of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]azetidine-1-carboxylate(300 mg, 640 umol) in THF (5 mL) was added Pd/C (100 mg, 71.2 mmol, 10%w/t) and Pd(OH)₂/C (100 mg, 71.2 mmol, 10% w/t) under N₂. The suspensionwas degassed under vacuum and purged with H₂ several times. The mixturewas stirred at 25° C. for 17 hours under H₂ (15 psi). On completion, themixture was filtered and concentrated in vacuo to give the titlecompound (240 mg, 79% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.07 (s, 1H), 7.07-6.98 (m, 2H), 6.87 (td, J=8.0 Hz, 1H), 5.33 (dd,J=12.8 Hz, 1H), 4.24-4.17 (m, 2H), 4.06-4.01 (m, 2H), 3.63 (s, 1H), 3.32(s, 3H), 3.27-3.24 (m, 2H), 2.68-2.64 (m, 2H), 1.99 (s, 2H), 1.86-1.79(m, 2H), 1.50 (t, J=7.2 Hz, 2H), 1.37 (s, 9H).

Step3—3-[5-[3-(Azetidin-3-yloxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]azetidine-1-carboxylate (220 mg, 465 umol) in DCM (5 mL) was added TFA(33.8 g, 297 mmol, 22.0 mL). The reaction mixture was stirred at 25° C.for 2 hours. On completion, the reaction mixture was concentrated invacuo to give the title compound (150 mg, 86% yield) as a yellow solid.LC-MS (ESI⁺) m/z 373.2 (M+H)⁺.

4-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-ylmethanesulfonate (Intermediate YX)

Step1—3-(5-(4-Hydroxybut-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HN) and but-3-yn-1-ol (207 mg, 2.96 mmol,CAS #927-74-2) in DMF (8 mL) was added Pd(PPh₃)₂Cl₂ (207 mg, 295 umol),Cs₂CO₃ (1.93 g, 5.91 mmol), CuI (56.3 mg, 295 umol) and 4Å molecularsieves at 25° C. under N₂. The mixture was then heated to 80° C. andstirred for 2 hours. On completion, the reaction mixture was quenched byaddition water (10 mL) at 25° C., and then diluted with CH₂Cl₂ (20 mL)and extracted with CH₂Cl₂ (3×20 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo to give a residue.The residue was purified by reverse phase (FA condition) to give thetitle compound (355 mg, 73% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 7.24 (s, 1H), 7.09 (s, 2H), 5.41-5.33 (m, 1H),4.88 (s, 1H), 3.58 (t, J=7.0 Hz, 2H), 3.33 (s, 3H), 2.91-2.84 (m, 1H),2.73-2.64 (m, 2H), 2.55 (t, J=7.0 Hz, 2H), 2.05-1.99 (m, 1H); LC-MS(ESI⁺) m/z 328.1 (M+H)⁺.

Step2—4-(1-(2,6-Dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)but-3-yn-1-ylmethanesulfonate

To a mixture of3-[5-(4-hydroxybut-1-ynyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(350 mg, 1.07 mmol) in DCM (10 mL) was added TEA (324 mg, 3.21 mmol) andMsCl (159 mg, 1.39 mmol) at 0° C. The mixture was stirred at 0° C. for0.5 hour. On completion, the reaction mixture was quenched by additionwater (20 mL) at 25° C., and then extracted with DCM (3×30 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (400 mg, 92% yield) asyellowish oil. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.09-7.06 (m, 1),7.00 (s, 1), 6.67 (d, J=8.2 Hz, 1H), 5.14-5.09 (m, 1H), 4.33 (t, J=6.8Hz, 2H), 3.35 (s, 3H), 3.00 (s, 3H), 2.82 (t, J=6.8 Hz, 2H); LC-MS(ESI⁺) m/z 406.3 (M+H)⁺.

3-[5-[4-[4-(Aminomethyl)-1-piperidyl]but-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate YY)

Step 1—Tert-ButylN-[[1-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]but-3-ynyl]-4-piperidyl]methyl]carbamate

To a solution of4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]but-3-ynylmethanesulfonate (350 mg, 863 umol, Intermediate YX) and tert-butylN-(4-piperidylmethyl)carbamate (222 mg, 1.04 mmol, CAS #135632-53-0) ina mixed solvent of CHCl₃ (5 mL) and ACN (5 mL) was added K₂CO₃ (239 mg,1.73 mmol). The reaction mixture was stirred at 65° C. for 12 hrs. Oncompletion, the mixture was diluted with water (50 mL), then extractedwith EA (2×50 mL). The organic layer was washed with brine (50 mL),dried with Na₂SO₄, filtrated and concentrated in vacuo. The residue waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 150*50 mm*10um; mobile phase: [water (0.225% FA)-ACN]; B %: 10%-40%, 10 min) to givethe title compound (165 mg, 37% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.23 (s, 1H), 7.11-7.06 (m, 2H), 6.83 (t,J=5.6 Hz, 1H), 5.37 (dd, J=5.2, 12.8 Hz, 1H), 3.32 (s, 3H), 2.95-2.84(m, 3H), 2.79 (t, J=6.4 Hz, 2H), 2.74-2.54 (m, 6H), 2.06-1.96 (m, 3H),1.64-1.54 (m, 2H), 1.36 (s, 9H), 1.35-1.31 (m, 1H), 1.17-1.04 (m, 2H).

Step2—3-[5-[4-[4-(Aminomethyl)-1-piperidyl]but-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[1-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]but-3-ynyl]-4-piperidyl]methyl]carbamate (90.0 mg, 172 umol) in DCM (5mL) was added ZnBr₂ (387 mg, 1.72 mmol). The reaction mixture wasstirred at 20° C. for 10 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (70.0 mg, 96% yield) asa white solid. LC-MS (ESI⁺) m/z 424.3 (M+H)⁺.

2-[2-[2-(Methylamino)ethoxy]ethyl]isoindoline-1,3-dione (IntermediateYZ)

Step 1—N-[2-(2-hydroxyethoxy)ethyl]formamide

A solution of 2-(2-aminoethoxy)ethanol (5.00 g, 47.5 mmol, CAS#929-06-6) in ethyl formate (18.4 g, 248 mmol, CAS #109-94-4) wasstirred at 90° C. for 6 hrs. On completion, the mixture was concentratedin vacuo to give the title compound (6.30 g, 99% yield) as yellow oil.LC-MS (ESI⁺) m/z 134.1 (M+H)⁺.

Step 2—2-[2-(Methylamino)ethoxy]ethanol

To a solution of LiAlH₄ (2.16 g, 56.7 mmol) in THF (30.0 mL) was added asolution of N-[2-(2-hydroxyethoxy)ethyl]formamide (6.30 g, 47.3 mmol) inTHF (30.0 mL) dropwise at 0° C. The mixture was stirred at 80° C. for 2hrs. On completion, the reaction mixture was quenched with a solution of15% NaOH (20 mL). Thereafter, 50 g anhydrous sodium sulfate was added,and the mixture was filtered. The filtrate was concentrated in vacuo togive the title compound (5.64 g, 100% yield) as yellow oil.

Step 3—Tert-butyl N-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate

To a solution of 2-[2-(methylamino)ethoxy]ethanol (5.60 g, 46.9 mmol) inMeOH (70.0 mL) was added (Boc)₂O (15.3 g, 70.4 mmol), the mixture wasstirred at 25° C. for 12 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gel column(PE:EA-2:1) to give the title compound (8.00 g, 77% yield) as colorlessoil. ¹H NMR (400 MHz, CDCl₃) δ 3.80-3.68 (m, 2H), 3.67-3.52 (m, 4H),3.48-3.33 (m, 2H), 2.92 (s, 3H), 1.47 (s, 9H).

Step 4—2-[2-[Tert-butoxycarbonyl(methyl)amino]ethoxy]ethylmethanesulfonate

To a solution of tert-butylN-[2-(2-hydroxyethoxy)ethyl]-N-methyl-carbamate (1.00 g, 4.56 mmol), TEA(1.38 g, 13.6 mmol) in DCM (10.0 mL) was added MsCl (783 mg, 6.84 mmol)at 0° C. The mixture was stirred at 20° C. for 1 hr. On completion, themixture was diluted with DCM (20 mL), washed with H₂O (3×20 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo to give the title compound (1.28 g, 94% yield) as yellow oil.¹H NMR (400 MHz, CDCl₃) δ 4.33-4.26 (m, 2H), 3.68-3.62 (m, 2H),3.59-3.48 (m, 2H), 3.39-3.28 (m, 2H), 2.98 (s, 3H), 2.84 (s, 3H), 1.39(s, 9H).

Step 5—Tert-ButylN-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethyl]-N-methyl-carbamate

To a solution of 2-[2-[tert-butoxycarbonyl(methyl)amino]ethoxy]ethylmethanesulfonate (1.08 g, 3.63 mmol) in DMF (10.0 mL) was added(1,3-dioxoisoindolin-2-yl)potassium (1.01 g, 5.45 mmol). The mixture wasstirred at 80° C. for 3 hrs. On completion, the mixture was diluted withH₂O (40 mL), then extracted with EA (3×30 mL). The organic layers werewashed with brine (2×30 mL) and dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gel column(PE:EA=5:1) to give the title compound (1.2 g, 94% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.89-7.83 (m, 4H), 3.81-3.71 (m, 2H),3.68-3.56 (m, 2H), 3.54-3.42 (m, 2H), 3.28-3.20 (m, 2H), 2.69 (s, 3H),1.32 (s, 9H).

Step 6—2-[2-[2-(Methylamino)ethoxy]ethyl]isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethyl]-N-methyl-carbamate (200mg, 574 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 4.00 mL).The mixture was stirred at 20° C. for 0.5 hr. On completion, the mixturewas concentrated in vacuo to give the title compound (160 mg, 97% yield,HCl) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (s, 1H), 7.92-7.84(m, 4H), 3.84-3.76 (m, 2H), 3.73-3.65 (m, 4H), 3.10-2.92 (m, 2H), 2.49(s, 3H).

Tert-ButylN-[[(2S)-4-(2-aminoethyl)morpholin-2-yl]methyl]-N-methyl-carbamate(Intermediate ZA)

Step 1—Tert-ButylN-[[(2S)-4-[2-(1,3-dioxoisoindolin-2-yl)ethyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of tert-butylN-methyl-N-[[(2S)-morpholin-2-yl]methyl]carbamate (1.00 g, 4.34 mmol,Intermediate YM) in ACN (30 mL) was added K₂CO₃ (535 mg, 13.0 mmol) and2-(2-bromoethyl)isoindoline-1,3-dione (1.21 g, 4.77 mmol, CAS #574-98-1)and KI (72.1 mg, 434 umol). The reaction mixture was stirred at 80° C.for 12 hrs. On completion, the mixture was diluted with H₂O (20 mL),then extracted with EA (2×20 mL). The combined organic layers werewashed with brine (2×20 mL), dried over anhydrous Na₂SO₄, filtered andthe filtrate was concentrated in vacuo. The residue was purified bysilica gel column (PE:EA=1:1) to give the title compound (1.75 g, 100%yield) as yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.89-7.81 (m, 2H),7.77-7.67 (m, 2H), 3.96-3.75 (m, 3H), 3.65-3.48 (m, 2H), 3.42-3.29 (m,1H), 3.14 (dd, J=6.4, 14.4 Hz, 1H), 2.89 (s, 3H), 2.86-2.73 (m, 2H),2.70-2.51 (m, 2H), 2.17 (t, J=10.4 Hz, 1H), 1.93-1.90 (m, 1H), 1.45 (s,9H).

Step 2—Tert-ButylN-[[(2S)-4-(2-aminoethyl)morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of tert-butylN-[[(2S)-4-[2-(1,3-dioxoisoindolin-2-yl)ethyl]morpholin-2-yl]methyl]-N-methyl-carbamate(1.00 g, 2.48 mmol) in EtOH (10 mL) was added NH₂NH₂—H₂O (633 mg, 12.4mmol). The reaction mixture was stirred at 80° C. for 2 hrs. Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (650 mg, 96% yield) asyellow solid. ¹H NMR (400 MHz, CDCl₃) δ 3.94-3.81 (m, 1H), 3.76-3.60 (m,2H), 3.53-3.30 (m, 1H), 3.24-3.09 (m, 1), 2.92 (s, 3H), 2.82-2.78 (m,2H), 2.75-2.71 (m, 1H), 2.68-2.65 (m, 1H), 2.43 (t, J=6.0 Hz, 2H),2.51-2.35 (m, 1H), 2.17-2.15 (1H), 1.88 (t, J=10.4 Hz, 1H), 1.46 (s,9H).

BenzylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]-N-[2-[(2R)-2-(methylaminomethyl)morpholin-4-yl]ethyl]carbamate(Intermediate ZB)

Step 1—Tert-ButylN-[[(2S)-4-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]ethyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde(400 mg, 1.04 mmol, Intermediate SK) and tert-butylN-[[(2S)-4-(2-aminoethyl)morpholin-2-yl]methyl]-N-methyl-carbamate (428mg, 1.57 mmol, Intermediate ZA) in a mixed solvent of THF (5 mL) and DMF(2 mL) was added HOAc (62 mg, 1.04 mmol). The reaction mixture wasstirred at 25° C. for 0.5 hr. Then, NaBH(OAc)₃ (266 mg, 1.25 mmol) wasadded. The reaction mixture was stirred at 25° C. for 12 hrs. Oncompletion, the mixture was quenched with water (0.5 mL) andconcentrated in vacuo. The crude product was purified by reverse phaseHPLC (0.1% FA condition) to give the title compound (410 mg, 61% yield)as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.24 (s, 1H),7.16-7.02 (m, 2H), 5.37 (dd, J=5.6, 12.8 Hz, 1H), 4.53-4.50 (m, 1H),3.91 (s, 2H), 3.80-3.75 (m, 2H), 3.35 (s, 3H), 3.23-3.17 (m, 2H),2.92-2.87 (m, 1H), 2.80-2.73 (m, 4H), 2.69-2.58 (m, 7H), 2.06-1.98 (m,2H), 1.82-1.74 (m, 1H), 1.36 (s, 9H).

Step 2—Tert-ButylN-[[(2S)-4-[2-[benzyloxycarbonyl-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]]amino]ethyl]morpholin-2-yl]methyl]-N-methyl-carbamate

To a solution of tert-butylN-[[(2S)-4-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]ethyl]morpholin-2-yl]methyl]-N-methyl-carbamate(100 mg, 184 umol) in THF (5 mL) was added TEA (55.7 mg, 550 umol).Then, CbzCl (47.0 mg, 275 umol) was added. The reaction mixture wasstirred at 25° C. for 1 hr. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (50.0 mg, 38% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.49-7.26 (m,5H), 7.11-6.90 (m, 3H), 5.36 (dd, J=5.2, 12.8 Hz, 1H), 5.13 (s, 2H),4.52 (s, 2H), 3.75-3.67 (m, 1H), 3.57-3.44 (m, 5H), 3.22-3.11 (m, 4H),2.96-2.90 (m, 1H), 2.79 (s, 2H), 2.73-2.66 (m, 2H), 2.62-2.55 (m, 3H),2.43-2.37 (m, 2H), 2.06-1.96 (m, 2H), 1.80-1.68 (m, 1H), 1.37 (s, 9H);LC-MS (ESI⁺) m/z 679.2 (M+H)⁺.

Step 3—BenzylN-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]-N-[2-[(2R)-2-(methylaminomethyl)morpholin-4-yl]ethyl]carbamate

To a solution of tert-butylN-[[(2S)-4-[2-[benzyloxycarbonyl-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]amino]ethyl]morpholin-2-yl]methyl]-N-methyl-carbamate(50.0 mg, 73.6 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL).The reaction mixture was stirred at 20° C. for 1 hr. On completion, themixture was concentrated in vacuo to give the title compound (45.0 mg,99% yield) as white solid. LC-MS (ESI⁺) m/z 579.2 (M+H)⁺.

3-[3-Methyl-2-oxo-5-[2-(4-piperidyl)ethynyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZD)

Step 1—Tert-Butyl4-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]ethynyl]piperidine-1-carboxylate

To a solution of tert-butyl 4-ethynylpiperidine-1-carboxylate (743 mg,3.55 mmol CAS #287192-97-6) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg, 1.77mmol, Intermediate HN) in DMF (20 mL) was added Pd(PPh₃)₂Cl₂(249 mg, 355 umol), CuI (67.6 mg, 355 umol), 4Å molecular sieves (80 mg)and Cs₂CO₃ (2.89 g, 8.87 mmol). The mixture was de-gassed and thenheated at 80° C. for 2 hrs. On completion, the reaction mixture wasconcentrated in vacuo. The crude product was purified by reversed-phaseHPLC (0.1% FA condition) to give the title compound (500 mg, 58% yield)as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.25 (s, 1H),7.09 (s, 2H), 5.37 (dd, J=5.6, 12.8 Hz, 1H), 3.70-3.59 (m, 2H),3.33-3.33 (m, 3H), 3.19-3.08 (m, 2H), 2.95-2.80 (m, 2H), 2.75-2.62 (m,2H), 2.07-1.98 (m, 1H), 2.00-1.81 (m, 2H), 1.56-1.45 (m, 2H), 1.40 (s,9H); LC-MS (ESI⁺) m/z 489.3 (M+Na)⁺.

Step2—3-[3-Methyl-2-oxo-5-[2-(4-piperidyl)ethynyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl4-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]ethynyl]piperidine-1-carboxylate (60.0 mg, 129 umol) in DCM (5 mL) was addedZnBr₂ (347 mg, 1.54 mmol, 77.2 uL). The mixture was stirred at 25° C.for 24 hrs. On completion, the mixture was concentrated in vacuo to givethe title compound (40.0 mg, 68% yield) as yellow solid. LC-MS (ESI⁺)m/z 367.1 (M+H)⁺.

Tert-Butyl (3R)-3-piperazin-1-ylpyrrolidine-1-carboxylate (IntermediateZE)

Step 1—Tert-Butyl (3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate

To a solution of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate(5.00 g, 26.7 mmol, CAS #101469-92-5) in DCM (80 mL) was added TEA (8.11g, 80.1 mmol) and MsCl (3.98 g, 34.7 mmol) at 0° C. The mixture was thenstirred at 25° C. for 0.5 hr. On completion, the reaction mixture waswashed with water (3×60 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound (7.00 g,95% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 5.30-5.23 (m,1H), 3.70-3.42 (m, 4H), 3.05 (s, 3H), 2.38-2.08 (m, 2H), 1.47 (s, 9H).

Step 2—Benzyl4-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]piperazine-1-carboxylate

To a solution of tert-butyl(3S)-3-methylsulfonyloxypyrrolidine-1-carboxylate (3 g, 11.3 mmol) andbenzyl piperazine-1-carboxylate (4.98 g, 22.61 mmol, CAS #31166-44-6) inACN (30 mL) was added TEA (3.43 g, 33.9 mmol) and KI (2.82 g, 16.9mmol). The mixture was stirred as 80° C. for 40 hrs. On completion, themixture was concentrated in vacuo to give a residue. The reactionmixture was diluted with water (30 mL) and extracted with EA (3×30 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (SiO₂, PE/EA=3/1) to give the title compound (1.35g, 30% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.28(m, 5H), 5.14 (s, 2H), 3.75-3.38 (m, 6H), 3.34-3.20 (m, 1H), 3.09-3.05(m, 1H), 2.86-2.70 (m, 1H), 2.61-2.31 (m, 4H), 2.12-2.05 (m, 1H),1.85-1.75 (m, 1H), 1.46 (s, 9H).

Step 3—Tert-Butyl (3R)-3-piperazin-1-ylpyrrolidine-1-carboxylate

To a solution of benzyl4-[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]piperazine-1-carboxylate(1.20 g, 3.08 mmol) in MeOH (20 mL) was added Pd/C (400 mg, 10 wt %)under N₂. The suspension was degassed under vacuum and purged with H₂three times. The mixture was stirred at 25° C. for 16 hours under H₂ (15psi). On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (780 mg, 96% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 3.76-3.48 (m, 2H), 3.30-3.19(m, 1H), 3.08 (t, J=9.2 Hz, 1H), 2.90 (t, J=4.4 Hz, 3H), 2.83-2.69 (m,1H), 2.62-2.34 (m, 4H), 2.13-2.02 (m, 1H), 1.73-1.67 (m, 1H), 1.45 (s,9H).

3-[3-Methyl-2-oxo-5-[[4-[(3R)-pyrrolidin-3-yl]piperazin-1-yl]methyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZF)

Step 1—Tert-Butyl(3R)-3-[4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]piperazin-1-yl]pyrrolidine-1-carboxylate

To a mixture of tert-butyl(3R)-3-piperazin-1-ylpyrrolidine-1-carboxylate (200 mg, 783umol,Intermediate ZE) in a mixed solvent of THF (4 mL) and DMF (0.2 mL) wasadded1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde(225 mg, 783 umol, Intermediate SK) and HOAc (9.41 mg, 156 umol). Themixture was stirred at 25° C. for 30 minutes. After that, NaBH(OAc)₃(331 mg, 1.57 mmol) was added. The mixture was stirred 25° C. for 72hours. On completion, the reaction mixture was quenched by water (10mL), and then extracted with EA (3×15 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by prep-HPLC (column: PhenomenexSynergi Max-RP 150*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN])to give the title compound (290 mg, 70% yield) as white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 7.11-6.91 (m, 3H), 5.35 (dd, J=5.2,12.8 Hz, 1H), 3.48 (s, 2H), 3.45 (s, 1H), 3.42-3.34 (m, 1H), 3.33 (s,3H), 3.21-3.10 (m, 1H), 2.98-2.84 (m, 2H), 2.75-2.59 (m, 3H), 2.45-2.3(m, 8H), 2.06-1.93 (m, 2H), 1.71-1.51 (m, 1H), 1.38 (s, 9H); LC-MS(ESI⁺) m/z 527.2 (M+H)⁺.

Step2—3-[3-Methyl-2-oxo-5-[[4-[(3R)-pyrrolidin-3-yl]piperazin-1-yl]methyl]benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl(3R)-3-[4-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]piperazin-1-yl]pyrrolidine-1-carboxylate (120 mg, 227 umol) inDCM (5 mL) was added HCl/dioxane (4 M, 2.28 mL). The mixture was stirredat 25° C. for 1 hr. On completion, the reaction mixture was concentratedin vacuo to give the title compound (105 mg, 99% yield, HCl) as whitesolid. LC-MS (ESI⁺) m/z 427.5 (M+H)⁺.

Tert-Butyl methyl(3-oxopropyl)carbamate (Intermediate ZG)

To a solution of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (1.00g, 5.28 mmol, CAS #98642-44-5) in DCM (20 mL) was added DMP (3.36 g,7.93 mmol) at 20° C. Then the reaction mixture was stirred at 20° C. for2 hours. On completion, the reaction mixture was diluted with petroleumether (10 mL) and stirred for 10 minutes, filtered and concentrated invacuo. The residue was purified by flash silica gel chromatography togive the title compound (750 mg, 50% yield) as colorless oil. ¹H NMR(400 MHz, CDCl₃) δ 9.78 (s, 1H), 3.53-3.47 (m, 2H), 2.85 (s, 3H),2.66-2.62 (m, 2H), 1.43 (s, 9H).

3-(3-Methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionehydrochloride (Intermediate ZH)

Step1—Tert-butyl4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

A mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (1.00g, 2.96 mmol, Intermediate HP), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate(1.19 g, 3.84 mmol, CAS #286961-14-6), XPhos-Pd-G3 (376 mg, 0.444 mmol),K₃PO₄ (1.88 g, 8.87 mmol) in dioxane (20 mL) and water (2 mL) wasdegassed and purged with N₂ three times. The mixture was stirred at 60°C. for 3 hours under N₂ atmosphere. On completion, the reaction mixturewas filtered and the filtrate was concentrated in vacuo. The residue waspurified by reverse phase (0.1% FA condition) to give the title compound(1.00 g, 75% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09(s, 1H), 7.10-6.95 (m, 2H), 6.82 (d, J=7.2 Hz, 1H), 5.40-5.35 (m, 1H),3.99 (s, 3H), 3.67-3.50 (m, 3H), 2.95-2.83 (m, 1H), 2.80-2.55 (m, 3H),2.43-2.30 (m, 3H), 2.05-1.95 (m, 1H), 1.44 (s, 9H); LC-MS (ESI⁺) m/z441.0 (M+H)⁺.

Step 2—Tert-Butyl4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate(900 mg, 2.04 mmol) in THF (270 mL) was added Pd/C (180 mg, 10 wt %)under N₂ atmosphere. The suspension was degassed and purged with H₂three times. The mixture was stirred at 30° C. for 48 hours under H₂ (50Psi.). On completion, the reaction mixture was filtered and concentratedin vacuo to give the title compound (900 mg, 92% yield) as white solid.LC-MS (ESI⁺) m/z 387.2 (M+H−56)⁺.

Step3—3-(3-Methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionehydrochloride

To a solution of tert-butyl4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidine-1-carboxylate(1.00 g, 2.26 mmol) in DCM (10 mL) was added HCl/dioxane (4 mol/L, 5mL). The reaction mixture was stirred at 25° C. for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo to give thetitle compound (900 mg, 88% yield) as white solid. LC-MS (ESI⁺) m/z343.2 (M+H)⁺.

3-(3-Methyl-4-(1-(3-(methylamino)propyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionehydrochloride (Intermediate ZI)

Step 1—Tert-Butyl(3-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-1-yl)propyl)(methyl)carbamate

To a solution of3-[3-methyl-2-oxo-4-(4-piperidyl)benzimidazol-1-yl]piperidine-2,6-dione(350 mg, 0.924 mmol, Intermediate ZH) in THF (5 mL) and DMF (1 mL) wasadded Et₃N (140 mg, 1.39 mmol). Then the reaction mixture was stirred at20° C. for 0.5 hour. Then HOAc (83.2 mg, 1.39 mmol) and tert-butylN-methyl-N-(3-oxopropyl)carbamate (580 mg, 2.04 mmol, Intermediate ZG)were added to the above mixture. The reaction mixture was stirred at 20°C. for 0.5 hour. NaBH(OAc)₃ (392 mg, 1.85 mmol) was added to thereaction mixture and stirred at 20° C. for 16 hours. On completion, thereaction mixture was quenched with water (0.5 mL) and concentrated invacuo. The residue was purified by reverse phase (0.1% FA condition) togive the title compound (450 mg, 83% yield) as off-white solid. LC-MS(ESI⁺) m/z 514.4 (M+H)⁺.

Step2—3-(3-Methyl-4-(1-(3-(methylamino)propyl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionehydrochloride

To a solution of tert-butylN-[3-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-1-piperidyl]propyl]-N-methyl-carbamate(450 mg, 0.876 mmol) in DCM (5 mL) was added HCl/EA (4 mol/L, 2 mL), thethe reaction mixture was stirred at 20° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo to give the titlecompound (390 mg, 99% yield) as a white solid. LC-MS (ESI⁺) m/z 414.3(M+H)⁺.

3-(3-Methyl-4-(3-((R)-2-(2-(methylamino)ethyl)morpholino)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionehydrobromide (Intermediate ZL)

Step 1—Benzyl(2-((2R)-4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)morpholin-2-yl)ethyl)(methyl)carbamate

A mixture of benzylN-methyl-N-[2-[(2R)-4-prop-2-ynylmorpholin-2-yl]ethyl]carbamate (700 mg,2.07 mmol, Intermediate TV),3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione(982 mg, 3.11 mmol, Intermediate HP), Pd(PPh₃)₂Cl₂ (145 mg, 0.207 mmol),CuI (39.4 mg, 0.207 mmol) and Cs₂CO₃ (1.35 g, 4.14 mmol) in DMF (10 mL)was degassed and purged with N₂ three times. Then the mixture wasstirred at 80° C. for 2 hours under N₂ atmosphere. On completion, thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by reverse phase (0.1% of FA condition)to give the title compound (1.10 g, 73% yield) as a yellow solid. ¹H NMR(400 MHz, CDCl₃) δ 11.11 (s, 1H), 7.40-7.30 (s, 5H), 7.13 (dd, J=16.0Hz, J=7.6 Hz, 2H), 7.06-6.95 (m, 1H), 5.47-5.32 (m, 1H), 5.05 (s, 2H),3.90-3.75 (m, 1H), 3.63 (s, 3H), 3.56 (s, 3H), 3.27-3.15 (m, 2H),2.90-2.80 (m, 5H), 2.75-2.55 (m, 4H), 2.35-2.25 (m, 1H), 2.10-1.95 (m,2H), 1.76-1.72 (m, 1H), 1.65-1.55 (m, 2H); LC-MS (ESI⁺) m/z 574.1(M+H)⁺.

Step 2—Benzyl(2-((2R)-4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propyl)morpholin-2-yl)ethyl)(methyl)carbamate

To a solution of benzylN-[2-[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]morpholin-2-yl]ethyl]-N-methyl-carbamate(1.00 g, 1.74 mmol) in THF (200 mL) was added Pd/C (200 mg, 5 wt %) andPd(OH)₂/C (200 mg, 10 wt %) under N₂ atmosphere. The suspension wasdegassed and purged with H₂ three times. The mixture was stirred at 20°C. for 48 hours under H₂ (15 psi). On completion, the reaction mixturewas filtered and concentrated in vacuo to give the title compound (1.00g, 99% yield) as yellow-white solid. LC-MS (ESI⁺) m/z 578.2 (M+H)⁺.

Step3—3-(3-Methyl-4-(3-((R)-2-(2-(methylamino)ethyl)morpholino)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dionehydrobromide

To a solution of benzylN-[2-[(2R)-4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propyl]morpholin-2-yl]ethyl]-N-methyl-carbamate (1.00 g, 1.73 mmol) inDCM (10 mL) was added HBr/HOAc (4 mL, 40% solution). The mixture wasstirred at 20° C. for 3 hours. On completion, the reaction mixture wasconcentrated in vacuo. Then the residue was purified by reverse phase(0.1% of FA condition) to give the title compound (700 mg, 64% yield) asoff-white solid. LC-MS (ESI⁺) m/z 444.4 (M+H)⁺.

3-[3-Methyl-2-oxo-5-[3-(4-piperidyloxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZM)

Step 1—Tert-Butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]piperidine-1-carboxylate

To a mixture of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (350mg, 1.04 mmol, Intermediate HN) and tert-butyl4-prop-2-ynoxypiperidine-1-carboxylate (371 mg, 1.55 mmol,Intermediate™) in DMF (20 mL) was added Pd(PPh₃)₂Cl₂ (72.6 mg, 103umol), CuI (39.4 mg, 207 umol), Cs₂CO₃ (1.35 g, 4.14 mmol) and 4Åmolecular sieves (200 mg, 1.04 mmol) in one portion at 25° C. under N₂.The reaction mixture was stirred at 80° C. for 2 hours. On completion,the reaction mixture was quenched by addition water (0.5 mL) at 25° C.,and then extracted with EA (3×20 mL). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, filtered and concentratedin vacuo to give a residue. The residue was purified by reverse phase(FA condition) to give the title compound (300 mg, 58% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.23-7.17 (m, 1H),7.12 (d, J=1.2 Hz, 1H), 6.75 (d, J=8.1 Hz, 1H), 5.24-5.17 (m, 1H), 4.43(s, 2H), 3.85-3.72 (m, 3H), 3.43 (s, 3H), 3.18-3.09 (m, 2H), 3.01-2.92(m, 1H), 2.90-2.67 (m, 2H), 2.30-2.20 (m, 1H), 1.94-1.86 (m, 2H),1.64-1.57 (m, 2H), 1.47 (s, 9H); LC-MS (ESI⁺) m/z 519.3 (M+Na)⁺.

Step 2—Tert-Butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]piperidine-1-carboxylate

To a solution of tert-butyl4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]piperidine-1-carboxylate (300 mg, 604 umol) in THF (4 mL) was added Pd/C(50 mg, 10 wt %) and Pd(OH)₂/C (50 mg, 10 wt %) under N₂. The suspensionwas degassed under vacuum and purged with H₂ three times. The mixturewas stirred at 25° C. for 2 hours under H₂ (15 psi). On completion, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give a residue. The residue was purified by reverse phase (FAcondition) to give the title compound (300 mg, 84% yield) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H), 6.95-6.85 (m, 2H), 6.73(d, J=8.2 Hz, 1H), 5.26-5.18 (m, 1H), 3.81-3.73 (m, 2H), 3.49-3.42 (m,6H), 3.15-3.05 (m, 2H), 2.99-2.82 (m, 2H), 2.75 (t, J=7.6 Hz, 3H),2.28-2.19 (m, 1H), 1.95-1.77 (m, 4H), 1.53 (d, J=8.8 Hz, 2H), 1.47 (s,9H); LC-MS (ESI⁺) m/z 401.0 (M+H−100)⁺.

Step3—3-[3-Methyl-2-oxo-5-[3-(4-piperidyloxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]piperidine-1-carboxylate (270 mg, 539 umol) in DCM (4 mL) was added TFA(1.84 g, 16.2 mmol) at 25° C. The mixture was stirred at 25° C. for 2hours. On completion, the reaction mixture was concentrated in vacuo togive a residue. The residue was purified by reverse phase (TFAcondition) to give the title compound (162 mg, 58% yield, TFA salt) as ayellow solid. LC-MS (ESI⁺) m/z 401.0 (M+H)⁺.

3-[4-[3-(Azetidin-3-yloxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZN)

Step 1—Tert-Butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]azetidine-1-carboxylate

To a mixture of tert-butyl 3-prop-2-ynoxyazetidine-1-carboxylate (499mg, 2.37 mmol, Intermediate YV) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HP) in DMF (3 mL) was added CuI (22.5 mg,118 umol), Cs₂CO₃ (1.93 g, 5.91 mmol), Pd(PPh₃)₂Cl₂ (83.0 mg, 118 umol)and 4Å molecular sieves (100 mg). The reaction mixture was stirred at80° C. for 4 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (400 mg, 72% yield) as brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.21-7.16 (m, 1H),7.14-7.11 (m, 1H), 7.06-7.01 (m, 1H), 5.42-5.37 (m, 1H), 4.49-4.45 (m,3H), 4.09-4.04 (m, 2H), 3.77-3.72 (m, 2H), 3.63 (s, 3H), 2.92-2.84 (m,1H), 2.73-2.62 (m, 2H), 2.07-2.00 (m, 1H), 1.37 (s, 9H).

Step 2—Tert-Butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]azetidine-1-carboxylate

To a mixture of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]azetidine-1-carboxylate (400 mg, 853 umol) in THF (10 mL)was added Pd/C (150 mg, 10 wt %) and Pd(OH)₂/C (150 mg, 10 wt %). Thereaction mixture was stirred at 25° C. for 12 hours under H₂ (15 Psi).On completion, the reaction mixture was filtered and concentrated invacuo to give the title compound (300 mg, 74% yield) as light yellowsolid. LC-MS (ESI⁺) m/z 417.2 (M+H−56)⁺.

Step3—3-[4-[3-(Azetidin-3-yloxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]azetidine-1-carboxylate (290 mg, 613.71 umol) in DCM (3 mL) was addedTFA (44.6 g, 391 mmol, 29.0 mL). The reaction mixture was stirred at 25°C. for 1 hour. On completion, the reaction mixture was concentrated invacuo to give the title compound (298 mg, 99% yield, TFA salt) as redoil. LC-MS (ESI⁺) m/z 373.2 (M+H)⁺.

3-[4-[3-(4-Piperidyloxy)propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione(Intermediate ZO)

Step 1—Tert-Butyl4-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate

To a solution 3-(4-bromopyrido[2,3-b]indol-9-yl)piperidine-2,6-dione(400 mg, 1.12 mmol, Intermediate XY) and tert-butyl4-prop-2-ynoxypiperidine-1-carboxylate (534 mg, 2.23 mmol,Intermediate™) in DMF (8 mL) was added Pd(PPh₃)₂Cl₂ (157 mg, 223 umol),CuI (42.5 mg, 223 umol), Cs₂CO₃ (1.82 g, 5.58 mmol) and 4Å molecularsieves (40 mg). The mixture was de-gassed and then heated at 80° C. for2 hrs. On completion, the reaction mixture was concentrated in vacuo.The crude product was purified by reverse phase HPLC (0.1% FA condition)to give the title compound (200 mg, 34% yield) as brown solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 8.42 (d,J=5.2 Hz, 1H), 7.72-7.64 (m, 1), 7.62-7.56 (m, 1), 7.36-7.33 (m, 1),7.32-7.29 (m, 1), 6.06 (s, 1H), 4.71(s, 2H), 3.88-3.84 (m, 1H),3.70-3.65 (m, 2H), 3.10-3.05 (m, 2H), 3.05-2.95 (m, 1H), 2.77-2.68 (m,1H), 2.61 (s, 1H), 2.20-2.11 (m, 1H), 1.96-1.88 (m, 2H), 1.52-1.44 (m,2H), 1.39 (s, 9H); LC-MS (ESI⁺) m/z 539.3 (M+Na)⁺.

Step 2—Tert-Butyl4-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-4-yl]propoxy]piperidine-1-carboxylate

To a solution of tert-butyl4-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate (200 mg, 387 umol in THF (5 mL) was addedPd(OH)₂ (40.0 mg, 10 wt %), Pd/C (40.0 mg, 10 wt %) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred at 25° C. for 15 hours under H₂ (15 psi). Oncompletion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (120 mg, 59% yield) aswhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 8.31 (d, J=5.2Hz, 1H), 8.24 (d, J=7.6 Hz, 1H), 7.67-7.58 (m, 1H), 7.55-7.47 (m, 1H),7.28 (t, J=7.6 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 6.18-5.92 (m, 1H),3.67-3.47 (m, 6H), 3.29 (s, 1H), 3.28-3.21 (m, 2H), 3.17-2.93 (m, 4H),2.15-2.07 (m, 1H), 2.03-1.93 (m, 2H), 1.86-1.76 (m, 2H), 1.39 (s, 9H),1.35 (s, 1H); LC-MS (ESI⁺) m/z 521.3 (M+Na)⁺.

Step3—3-[4-[3-(4-Piperidyloxy)propyl]pyrido[2,3-b]indol-9-yl]piperidine-2,6-dione

To a mixture of tert-butyl 4-[3-[9-(2,6-dioxo-3-piperidyl)pyrido[2,3-b]indol-4-yl]propoxy]piperidine-1-carboxylate(100 mg, 192 umol) in DCM (2 mL) was added HCl/dioxane (2 mL). Thereaction mixture was stirred at 25° C. for 2 hrs. On completion, thereaction mixture was concentrated in vacuo to give the title compound(80.0 mg, 91% yield) as brown solid. LC-MS (ESI⁺) m/z 421.3 (M+H)⁺.

3-[3-Methyl-4-[3-[2-(methylamino)ethoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZP)

Step 1—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethyl]-N-methyl-carbamate

3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HP), tert-butylN-methyl-N-(2-prop-2-ynoxyethyl)carbamate (440 mg, 2.06 mmol,Intermediate GK), Pd(PPh₃)₂Cl₂ (166 mg, 237 umol), CuI (45.1 mg, 237umol), 4 Å molecular sieves (400 mg) and Cs₂CO₃ (1.54 g, 4.73 mmol) inDMF (5 mL) was de-gassed and then heated at 80° C. for 2 hours under N₂.On completion, the reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by reversed-phase (0.1%FA condition) to give the title compound (310 mg, 39% yield) as a yellowsolid. LC-MS (ESI⁺) m/z 415.1 (M+H−56)⁺.

Step 2—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethyl]-N-methyl-carbamate

To a solution of tert-butylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethyl]-Nmethyl-carbamate(390 mg, 829 umol) in THF (10 mL) was added Pd/C (0.1 g, 10% wt) andPd(OH)₂/C (0.1 g, 20% wt). The suspension was degassed under vacuum andpurged with H₂ several times. The reaction mixture was stirred at 25° C.for 12 hours under H₂ (15 psi). On completion, the mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(390 mg, 99% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.25(s, 1H), 7.12-6.96 (m, 1H), 6.95-6.86 (m, 1H), 6.72-6.60 (m, 1H),5.30-5.15 (m, 1H), 3.48 (s, 3H), 3.65-3.58 (m, 2H), 3.52-3.45 (m, 2H),3.45-3.35 (m, 2H), 3.08-2.95 (m, 3H), 2.92 (s, 3H), 2.85-2.60 (m, 2H),2.25-2.15 (m, 1H), 1.96-1.85 (m, 2H), 1.50 (s, 1H); LC-MS (ESI⁺) m/z375.1 (M+H−100)⁺.

Step3—3-[3-Methyl-4-[3-[2-(methylamino)ethoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethyl]-N-methyl-carbamate (100 mg, 211 umol) in DCM (2 mL) wasadded HCl/dioxane (2 mL). The reaction mixture was stirred at 20° C. for2 hrs. On completion, the mixture was concentrated in vacuo to give thetitle compound (85.0 mg, 98% yield, HCl salt) as a yellow solid. LC-MS(ESI⁺) m/z 375.1 (M+H)⁺.

3-[3-Methyl-5-[3-[3-(methylamino)propoxy]prop-1-ynyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZQ)

To a solution of tert-butylN-[3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]propyl]-N-methyl-carbamate(200 mg, 412 umol, synthesized via Step 1 of Intermediate QI) in DCM(3.00 mL) was added ZnBr₂ (1.39 g, 6.19 mmol). The mixture was stirredat 20° C. for 20 hrs. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (158 mg, 99% yield) asyellow solid. LC-MS (ESI⁺) m/z 385.2 (M+H)⁺.

3-[3-Methyl-5-[[4-(methylaminomethyl)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZR)

Step 1—Tert-ButylN-[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]-4-piperidyl]methyl]-N-methylcarbamate

To a solution of tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate (119mg, 522 umol, CAS #138022-04-5) and1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde(150 mg, 522 umol, Intermediate SK) in a mixed solvents of DMF (1.2 mL)and THF (2.4 mL) was added HOAc until the pH=5˜ 6. After the reactionmixture was stirred at 10° C. for 1 hr, then NaBH(OAc)₃ (221 mg, 1.04mmol) was added. Then the reaction mixture was stirred at 10° C. for 48hrs. On completion, the reaction mixture was quenched by H₂O (0.5 mL),filtered and the filtrate was concentrated in vacuo to give a residue.The residue was purified by reverse phase (0.1% FA condition) to givethe title compound (230 mg, 88% yield) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.53 (s, 1H), 7.21 (d, J=16.0 Hz, 1H), 7.01 (J=8.0 Hz,1H), 6.76 (d, J=8.0 Hz, 1H), 5.24 (dd, J=5.2, 12.8 Hz, 1H), 4.06-3.80(m, 2H), 3.43 (s, 3H), 3.24 (d, J 8.0 Hz, 2H), 3.13 (s, 2H), 2.98-2.87(m, 1H), 2.87 (s, 3H), 2.79 (d, J 4.8 Hz, 1H), 2.77-2.63 (m, 1H),2.57-2.39 (m, 1H), 2.37-2.16 (m, 2H), 1.91-1.78 (m, 1H), 1.78-1.60 (m,2H), 1.60-1.48 (m, 1H), 1.44 (s, 9H); LC-MS (ESI⁺) m/z 500.4 (M+H)⁺.

Step2—3-[3-Methyl-5-[[4-(methylaminomethyl)-1-piperidyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[[1-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methyl]-4-piperidyl]methyl]-N-methyl-carbamate (230 mg, 460 umol) in DCM(3 mL) was added HCl/dioxane (4 M, 3 mL). The reaction mixture wasstirred at 20° C. for 2 hrs. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (200 mg, 99% yield,HCl) as a white solid. LC-MS (ESI⁺) m/z 400.3 (M+H)⁺.

3-[3-Methyl-5-[3-[2-(methylamino)ethoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZS)

Step 1—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethyl]-N-methyl-carbamate

To a solution tert-butyl N-methyl-N-(2-prop-2-ynoxyethyl)carbamate (946mg, 4.44 mmol, Intermediate GK) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg, 1.77 mmol, Intermediate HN) in DMF (10 mL) was added Pd(PPh₃)₂Cl₂(249 mg, 355 umol), CuI (67.6 mg, 355 umol), 4 Å molecular sieves (80.0mg, 305 umol) and Cs₂CO₃ (2.89 g, 8.87 mmol). The reaction mixture wasstirred at 80° C. for 4 hrs. On completion, the reaction mixture wasconcentrated in vacuo. The crude product was purified by reverse phaseHPLC (0.1% FA condition) to give the title compound (540 mg, 52% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.31 (s,1H), 7.18-7.12 (m, 2H), 5.38 (dd, J=5.6, 12.4 Hz, 1H), 4.39 (s, 2H),3.62 (t, J=5.6 Hz, 2H), 3.38-3.36 (m, 2H), 3.34 (s, 3H), 2.82 (s, 3H),2.77-2.70 (m, 1H), 2.65-2.58 (m, 2H), 2.08-2.00 (m, 1H), 1.39 (s, 9H);LC-MS (ESI⁺) m/z 493.3 (M+Na)⁺.

Step 2—Tert-ButylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl]-N-methyl-carbamate

To a solution of tert-butylN-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethyl]-N-methyl-carbamate (530 mg, 1.13 mmol) in THF (5 mL)was added Pd/C (40.0 mg, 10 wt %), Pd(OH)₂ (40.0 mg, 10 wt %) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. The mixture was stirred at 25° C. for 15 hours under H₂ (15 psi).On completion, the reaction mixture was filtered and concentrated invacuo to give the title compound (450 mg, 84% yield) as yellow oil. ¹HNMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.04-6.97 (m, 2H), 6.85 (d,J=8.0 Hz, 1H), 5.33 (dd, J=4.8, 12.4 Hz, 1H), 3.48-3.43 (m, 2H),3.38-3.30 (m, 3H), 2.82 (s, 3H), 2.72-2.61 (m, 4H), 2.33 (s, 1H), 2.07(s, 4H), 2.04-1.96 (m, 1H), 1.86-1.74 (m, 2H), 1.38 (s, 9H); LC-MS(ESI⁺) m/z 497.3 (M+Na)⁺.

Step3—3-[3-Methyl-5-[3-[2-(methylamino)ethoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl]-N-methyl-carbamate (430 mg, 906 umol) in DCM (2 mL) wasadded HCl/dioxane (2 mL). The mixture was stirred at 25° C. for 2 hrs.On completion, the reaction mixture was concentrated in vacuo to givethe title compound (330 mg, 78% yield) as white solid. LC-MS (ESI⁺) m/z375.2 (M+H)⁺.

Tert-Butyl N-methyl-N-(3-vinyloxypropyl)carbamate (Intermediate ZT)

To a mixture of tert-butyl N-(3-hydroxypropyl)-N-methyl-carbamate (5.00g, 26.4 mmol, CAS #98642-44-5) and vinyl acetate (3.41 g, 39.6 mmol, CAS#108-05-4) in toluene (20 mL) was added chloroiridium(1Z,5Z)-cycloocta-1,5-diene (177 mg, 264 umol, CAS #12112-67-3) andNa₂CO₃ (1.68 g, 15.8 mmol) at 25° C. under N₂ in glove box. The mixturewas stirred at 100° C. for 2 hours. On completion, the reaction mixturewas quenched with water (20 mL), filtered and the filtrate was extractedwith EA (2×25 mL). The combined organic layers were washed with brine(10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give aresidue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=30/1) to afford the title compound (2.40g, 42% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 6.51-6.42 (m,1H), 4.21-4.13 (m, 1H), 4.02-3.96 (m, 1H), 3.69 (t, J=6.2 Hz, 2H), 3.32(s, 2H), 2.86 (s, 3H), 1.94-1.80 (m, 2H), 1.46 (s, 9H).

3-[3-Methyl-5-[2-[3-(methylamino)propoxy]ethyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(Intermediate ZU)

Step 1—Tert-ButylN-[3-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]ethoxy]propyl]-N-methyl-carbamate

To a solution of tert-butyl N-methyl-N-(3-vinyloxypropyl)carbamate (900mg, 4.18 mmol, Intermediate ZT) in THF (10 mL) was added 9-BBN (0.5 M,8.36 mL). The mixture was stirred at 25° C. for 2 hours. Then a solutionof 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (471mg, 1.39 mmol, Intermediate HN), K₃PO₄ (739 mg, 3.48 mmol) andditert-butyl(cyclopentyl)phosphane; dichloro palladium; iron (90.8 mg,139 umol) in DMF (15 mL) and H₂O (3 mL) was added to the above mixture.The reaction mixture was stirred at 75° C. for 20 minutes under N₂. Oncompletion, the reaction mixture was diluted with EA (100 mL), pouredinto water (50 mL) and extracted with EA (2×50 mL). The combined organiclayers were dried with Na₂SO₄, filtrated and concentrated in vacuo. Theresidue was purified by reverse phase (0.1% FA) to give the titlecompound (300 mg, 45% yield) as a light yellow solid. LC-MS (ESI⁺) m/z375.3 (M+H−100)⁺.

Step2—3-[3-Methyl-5-[2-[3-(methylamino)propoxy]ethyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butylN-[3-[2-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]ethoxy]propyl]-N-methyl-carbamate (200 mg, 421 umol) in DCM (2 mL) wasadded TFA (30.8 g, 270 mmol, 20 mL). The reaction mixture was stirred at25° C. for 1 hour. On completion, the reaction mixture was concentratedin vacuo to give the title compound (200 mg, 91% yield, 94% purity, TFA)as yellow oil. LC-MS (ESI⁺) m/z 375.3 (M+H)⁺.

4-[2-[2-(2-Aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate ZY) Step 1—Tert-ButylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]carbamate

A solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate(2.50 g, 10.1 mmol),2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (3.34 g, 12.1mmol) and diisopropyl ethylamine (2.60 g, 20.1 mmol) in dioxane (120 mL)was stirred at 115° C. for 16 hours. On completion, the reaction mixturewas concentrated in vacuo. The residue was purified by columnchromatography (petroleum ether:ethyl acetate=1:1) to give the titlecompound (2.10 g, 40% yield) as yellow gum. ¹H NMR (400 MHz, CDCl₃) δ8.50 (s, 1H), 7.54-7.48 (m, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.92 (d, J=8.4Hz, 1H), 6.59-6.48 (m, 1H), 5.15-5.00 (m, 1H), 4.95-4.85 (m, 1H),3.79-3.71 (m, 2H), 3.70-3.62 (m, 4H), 3.60-3.54 (m, 2H), 3.52-3.45 (m,2H), 3.35-3.25 (m, 2H), 2.92-2.71 (m, 3H), 2.19-2.09 (m, 1H), 1.44 (s,9H); LC-MS (ESI⁺) m/z 527.1 (M+Na)⁺.

Step2—4-[2-[2-(2-Aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(Intermediate ZY)

To a solution of tert-butylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]carbamate (200 mg, 396 umol) in DCM (5 mL) was addedHCl/dioxane (4 M, 5 mL). The reaction mixture was stirred at 25° C. for10 minutes. On completion, the reaction mixture was concentrated invacuo to give the title compound (200 mg, crude) as yellow solid. Thecrude product was used to next step directly without furtherpurification. LC-MS (ESI⁺) m/z 405.2 (M+H)⁺.

Methods

Example 1 (Method 1):6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-9,12,15-trioxa-3-azaicosan-20-yl)carbamoyl)cyclohexyl)nicotinamide,I−1

Step 1—Tert-Butyl (1-((1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4(cyclopropylamino)-nicotinamido)-cyclohexyl)-1-oxo-8,11,14-trioxa-2-azanonadecan-19-yl)carbamate

To a stirred suspension of(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicacid (0.2 g, 0.5 mmol, Intermediate C) and tert-butyl(5-(2-(2-((5-aminopentyl)oxy)ethoxy)ethoxy)pentyl)carbamate (0.25 g,0.67 mmol, Intermediate B) in DMF (2 mL) was added DIPEA (0.4 mL, 2.2mmol) and PyBOP (0.35 g, 0.67 mmol) at rt. The resulting reactionmixture was stirred at rt for 1 h. The reaction mixture was transferredinto ice water and the resulting mixture was extracted using ethylacetate (3×20 mL). The combined organic layers were dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure and the crude product was purified using silica gel columnchromatography (10% MeOH-DCM) to give tert-butyl(1-((1r,4r)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexyl)-1-oxo-8,11,14-trioxa-2-azanonadecan-19-yl)carbamateas a brown solid (0.18 g, 50%). LC-MS (ESI⁺) m/z 804.1 (M−H)⁻

Step2—6-((1,6-naphthyridin-2-yl)amino)-N-((1R,4R)-4-((5-(2-(2-((5-aminopentyl)oxy)ethoxy)-ethoxy)-pentyl)carbamoyl)cyclohexyl)-4-(cyclopropylamino)nicotinamideHydrochloride

To a stirred solution of tert-butyl(1-((1r,4r)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexyl)-1-oxo-8,11,14-trioxa-2-azanonadecan-19-yl)-carbamate(0.18 g, 0.22 mmol) in 1,4 dioxane (3 mL) was added 4N HCl in dioxane (1mL) at 0° C. The resulting reaction mixture was warmed to rt and stirredfor 2 h. The reaction mixture was evaporated under vacuum and trituratedusing diethyl ether to give6-((1,6-naphthyridin-2-yl)amino)-N-((1r,4r)-4-((5-(2-(2-((5-aminopentyl)oxy)ethoxy)ethoxy)pentyl)carbamoyl)-cyclohexyl)-4-(cyclopropylamino)nicotinamidehydrochloride as yellow solid (0.16 g, 96%). LCMS (ESI⁺) m/z 706.6(M+H)⁺.

Step3—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-9,12,15-trioxa-3-azaicosan-20-yl)carbamoyl)cyclohexyl)nicotinamide

To a solution of2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetic acid(0.085 g, 0.24 mmol, Intermediate D) in DMF (5 mL) was added HATU (0.14g, 0.36 mmol) at 0° C. and the reaction mixture was stirred for 30minutes. To this reaction mixture,6-((1,6-naphthyridin-2-yl)amino)-N-((1r,4r)-4-((5-(2-(2-((5-aminopentyl)oxy)ethoxy)ethoxy)pentyl)-carbamoyl)-cyclohexyl)-4-(cyclopropylamino)nicotinamidehydrochloride (0.18 g, 0.24 mmol) and DIPEA (0.15 mL, 0.72 mmol) wasadded at 0° C. The resulting reaction mixture was warmed to rt andstirred for 1 h. The reaction mixture was transferred into ice water,and the resulting precipitate was filtered off and washed with water anddried under reduced pressure. The crude product was purified usingpreparative HPLC (0.1% formic acid in water/ACN) to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,4r)-4-((1-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)-2-oxo-9,12,15-trioxa-3-azaicosan-20-yl)carbamoyl)cyclohexyl)-nicotinamideI−1 as off white solid (0.04 g, 16%). ¹H NMR (400 MHz, DMSO) δ 11.11 (s,1H), 10.34 (s, 1H), 9.02 (s, 1H), 8.55-8.53 (m, 3H), 8.40 (s, 1H), 8.24(d, J=9.2 Hz, 1H), 8.13-8.11 (m, 1H), 7.96-7.93 (m, 1H), 7.79 (t, J=7.6Hz, 1H), 7.78-7.69 (m, 1H), 7.54 (d, J=5.6 Hz, 1H), 7.49-7.46 (m, 2H),7.36 (d, J=8.4 Hz, 1H), 5.12-5.09 (m, 1H), 4.75 (s, 2H), 3.72 (bs, 1H),3.48-3.47 (m, 7H), 3.14-3.09 (m, 2H), 2.99-2.98 (m, 2H), 2.96-2.94 (m,1H), 2.59-2.52 (m, 2H), 2.03-2.0 (m, 2H), 1.85-1.83 (m, 2H), 1.73-1.71(m, 2H), 1.45-1.42 (m, 6H), 1.40-1.38 (m, 2H), 1.36-1.34 (m, 2H),1.31-1.28 (m, 1H), 1.25-1.24 (m, 4H), 0.92-0.91 (m, 2H), 0.56 (s, 2H).LC-MS (ESI⁺) m/z 1020.2 (M+H)⁺.

TABLE 2 Compounds synthesized via Method 1, with the coupling of variousamines with acid Intermediate C in Step 1, followed by coupling withacid Intermediate D in Step 3. LCMS Intermediate (ES+) m/z Ex-# I-#Amine (M + H)+ HNMR (400 MHz, DMSO-d6) δ 2  I-2 E 932.2 11.15 (s, 1H),10.37 (s, 1H), 9.05 (s, 1H), 8.42 (s, 1H), 8.33-8.26 (m, 2H), 8.15 (d, J= 7.6 Hz, 1H), 7.98 (s, 1H), 7.81 (t, J = 8 Hz, 2H), 7.57-7.49 (m, 3H),7.38 (d, J = 8.4 Hz, 1H), 5.15-5.10 (m, 2H), 4.77 (s, 1H), 3.16- 2.87(m, 6H), 2.05-2.02 (m, 4H), 1.87-1.72 (m, 5H), 1.46-1.23 (m, 18H),0.94-0.85 (m, 4H), 0.58 (s, 2H) 3  I-3 tert-butyl (5- 845.8 11.14 (s,1H), 10.37 (s, 1H), 9.04 (s, 1H), 8.65-8.45 (m, aminopentyl)carbamate3H), 8.40 (s, 1H), 8.23 (d, J = 9.2 Hz, 1H), 8.18-8.05 (CAS# (m, 2H),7.98-7.88 (m, 1H), 7.81 (t, J = 8.0 Hz, 1H), 51644-96-3) 7.75-7.65 (m,1H), 7.63-7.53 (m, 1H), 7.52-7.42 (m, 2H), 7.38 (d, J = 8.4 Hz, 1H),5.05-5.15 (m, 1H), 4.76 (s, 2H), 3.75-3.61 (m, 1H), 3.18-3.08 (m, 2H),3.15- 2.95 (m, 2H), 2.94-2.81 (m, 1H), 2.61-2.51 (m, 3H), 2.11-1.97 (m,2H), 1.90-1.80 (m, 2H), 1.79-1.70 (m, 2H), 1.50-1.20 (m, 10H), 0.92 (d,J = 5.2 Hz, 2H), 0.57 (s, 2H) 4^(a) I-4 tert-butyl (5- 845.0 11.18 (s,1H), 10.38 (s, 1H), 9.05 (s, 1H), 8.57-8.56 (m, aminopentyl)carbamate3H), 8.42(s, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.15 (s, 1H), (CAS# 8.14 (d,J = 2.8 Hz, 1H), 7.96 (t, J = 5.2 Hz, 1H), 7.83 51644-96-3) (t, J = 7.2Hz, 1H), 7.72 (t, J = 5.2 Hz, 1H), 7.57 (d, J = 6 Hz, 1H), 7.51 (d, J =7.6 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 5.16-5.12 (m, 1H), 4.77 (s, 2H),3.67 (bs, 2H), 3.41-3.12 (m, 2H), 3.02-2.94 (m, 2H), 2.90-2.86 (m, 2H),2.60-2.51 (m, 3H), 2.08-2.03 (m, 2H), 1.87 (d, J = 10 Hz, 2H), 1.76 (d,J = 10.4 Hz, 2H), 1.46-1.23 (m, 11H), 0.95-0.93 (m, 2H), 0.59 (s, 2H) 5 I-5 F 976.1 11.11 (s, 1H), 10.34 (s, 1H), 9.03 (s, 1H), 8.55-8.53 (m,3H), 8.40 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 8.15 (s, 1H), 8.13 (d, J =7.6 Hz, 1H), 7.94 (t, J = 5.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.69(t, J = 5.2 Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.49-7.46 (m, 2H), 7.37(d, J = 8.8 Hz, 1H), 3.70-3.60 (m, 1H), 3.43 (s, 3H), 3.12 (d, J = 6.0Hz, 2H), 2.99 (d, J = 6.0 Hz, 2H), 2.90-2.80 (m, 1 H), 2.59-2.55 (m,2H), 2.10-1.95 (m, 2H), 1.90-1.95 (m, 4H), 1.50-1.20 (m, 16H), 0.92 (d,J = 5.2 Hz, 2H), 0.56 (s, 2H) 6^(b) I-6 tert-butyl (2-(2- 847.8 11.1 (s,1H), 9.51 (s, 1H), 8.94 (s, 1H), 8.81 (d, J = 6.0aminoethoxy)ethyl)carbamate Hz, 1H), 8.8-8.7 (m, 1H), 8.65 (d, J = 8.8Hz, 1H), 8.50 (CAS# (s, 1H), 8.32-8.22 (m, 1H), 8.05 (d, J = 5.4 Hz,1H), 127828-22-2) 7.83-7.78 (m, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.49 (d,J = 7.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 2H), 5.12 (dd, J = 12.8 Hz & 5.4Hz, 1H), 4.79 (s, 2H), 3.7-3.6 (m, 2H), 3.46- 3.43 (m, 2H), 3.41-3.37(m, 2H), 3.33-3.30 (m, 2H), 3.22-3.15 (m, 2H), 3.22-3.15 (m, 2H),3.95-3.80 (m, 1H), 3.70-3.55 (m, 1H), 2.15-2.01 (m, 2H), 1.90-1.81 (m,2H), 1.80-1.70 (m, 2H), 1.49-1.22 (m, 4H), 0.93 (d, J = 5.6 Hz, 2H),0.67 (s, 2H) 7^(a) I-7 tert-butyl (3- 816.9 11.18 (s, 1H), 9.50 (s, 1H),8.57-8.56 (m, 3H), 8.42 (s, aminopropyl)carbamate 1H), 8.27(d, J = 8.8Hz, 1H), 8.15-8.13 (m, 2H), 8.00 (t, (CAS# J = 6 Hz, 1H), 7.82 (t, J = 8Hz, 1H), 7.75 (t, J = 1.3 75178-96-0) Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H),7.51 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.15-5.10 (m, 1H),4.79 (s, 2H), 3.68 (bs, 1H), 3.15 (d, J = 1.3 Hz, 2H), 3.05 (d, J = 6Hz, 2H), 2.94-2.87 (m, 3H), 2.05-2.02 (m, 2H), 1.87-1.85 (m, 2H),1.77-1.74 (m, 2H), 1.57 (t, J = 6.4 Hz, 2H), 1.47-1.30 (m, 5H), 0.94 (d,J = 5.2 Hz, 2H), 1.94 (s, 2H) 8^(b) I-8 tert-butyl (2- (M − H)⁻ 11.14(s, 1H), 10.36 (s, 1H), 9.05 (s, 1H), 8.65-8.55 (m, aminoethyl)carbamate801.8 3H), 8.42 (s, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.18-8.08 (CAS# (m,2H), 8.1-8.0 (m, 1H), 7.89-7.79 (m, 2H), 7.57 (d, J = 57260-73-8) 5.6Hz, 1H), 7.55-7.45 (m, 1H), 7.40 (d, J = 8.4 Hz, 1H), 5.15-5.10 (m, 1H),4.78 (s, 2H), 3.19-3.11 (m, 3H), 3.0-2.75 (m, 3H), 2.65-2.55 (m, 1H),2.11-2.95 (m, 3H), 2.90-2.80 (m, 2H), 2.79-2.70 (m, 2H), 1.50-1.20 (m,5H), 0.94 (d, J = 5.6 Hz, 2H), 0.58 (s, 2H) 9^(b) I-9 tert-butyl (4-831.7 11.12 (s, 1H), 10.34 (s, 1H), 9.03 (s, 1H), 8.86-8.53 (m,aminobutyl)carbamate 2H), 8.40 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H),8.15-8.05 (CAS# (m, 2H), 7.97 (t, J = 5.6 Hz, 1H), 7.81 (t, J = 7.8 Hz,68076-36-8) 1H), 7.72 (t, J = 5.6 Hz, 2H), 7.54 (d, J = 6.0 Hz, 1H),7.49 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 9.6 Hz, 1H), 5.11 (dd, J = 12.8Hz & 5.2 Hz, 1H), 4.76 (s, 2H), 3.75-3.6 (m, 1H), 3.2-3.11 (m, 2H),3.1-2.99 (m, 2H), 2.98-2.80 (m, 1H), 2.65-3.5 (m, 3H), 2.10-2.0 (m, 2H),1.9-1.7 (m, 4H), 1.5-1.2 (m, 8H), 0.92 (d, J = 4.8 Hz, 2H), 0.57 (s, 2H)*The intermediate formed in Step 1-2 could be triturated with diethylether, MBTE, or n-pentanes. Step 1 was run for 1-2 h. ^(a)Step 2 startedat 0° C. then run at rt for 6 h; Step 3 was run for 4 h at rt. ^(b)Oncewater was added to quench the reaction in Step 1, the productprecipitated out of solution and was collected, dried and used directlyin the next step. For Step 3, PyBOP was used as the coupling reagentinstead of HATU and the reaction was run at rt for 1 hr.

Example 10 (Method 2):6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1S,4r)-4-((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamoyl)cyclohexyl)-nicotinamide,I-10

Step 1—Tert-Butyl(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamate

To a solution of 7-((tert-butoxycarbonyl)amino)heptanoic acid (0.3 g,1.2 mmol, CAS #60142-89-4),(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-benzyl)pyrrolidine-2-carboxamidehydrochloride (0.74 g, 1.59 mmol, Intermediate G) and DIPEA (1.1 mL, 6.1mmol) in DMF (2 mL) was added PyBOP (0.95 g, 1.5 mmol) at rt and themixture was stirred for 2 h. The reaction mixture was then transferredinto ice water and the resulting mixture was extracted using ethylacetate (3×20 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure and the crude product was purified using silica gel columnchromatography (4% MeOH-DCM) to give tert-butyl(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)-pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamateas brownish yellow semisolid (0.8 g, 99%). LC-MS (ESI⁺) m/z 658.7(M+H)⁺.

Step2—(2S,4R)-1-((S)-2-(7-aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride

To a stirred solution of tert-butyl(7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamate(0.8 g, 1.2 mmol) in DCM (10 mL) was added 4N HCl in dioxane (2 mL) at0° C. The resulting reaction mixture was warmed to rt and stirred for 2h. The reaction mixture was then evaporated under vacuum and trituratedusing diethyl ether to give(2S,4R)-1-((S)-2-(7-aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)-pyrrolidine-2-carboxamidehydrochloride as yellow solid (0.5 g, 70%). LCMS (ESI⁺) m/z 558.61(M+H)⁺.

Step3—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1S,4r)-4-((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamoyl)cyclohexyl)nicotinamide

To a stirred suspension of(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicacid (0.2 g, 0.5 mmol, Intermediate C) and(2S,4R)-1-((S)-2-(7-aminoheptanamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidehydrochloride (0.34 g, 0.58 mmol) in DMF (5 mL) was added DIPEA (0.5 mL,2.3 mmol) and PyBOP (0.35 g, 0.68 mmol) and the reaction mixture wasstirred at rt for 1 h. The reaction mixture was then transferred intoice water and the resulting mixture was extracted using ethyl acetate(3×20 mL). The combined organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the crude product was purified using preparative HPLC (0.1% formicacid in water/ACN) to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1S,4r)-4-((7-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-7-oxoheptyl)carbamoyl)cyclohexyl)nicotinamideI-10 as light yellow solid (0.21 g, 37%). ¹H NMR (400 MHz, DMSO) δ 10.36(s, 1H), 9.05 (s, 1H), 8.99 (s, 1H), 8.63-8.51 (m, 3H), 8.42 (s, 1H),8.27 (d, J=9.2 Hz, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H),7.71-7.63 (m, 1H), 7.57 (d, J=5.6 Hz, 1H), 7.51 (d, J=8.8 Hz, 1H),7.48-7.31 (m, 3H), 4.55 (d, J=9.2 Hz, 1H), 4.49-4.41 (m, 1H), 4.40-4.31(m, 2H), 4.30-4.15 (m, 1H), 3.75-3.61 (m, 2H), 3.05-2.95 (m, 2H),2.65-2.55 (m, 1H), 2.45 (s, 3H), 2.41-1.71 (m, 8H), 1.51-1.21 (m, 10H),0.94 (s, 9H), 0.55 (s, 2H). LC-MS (ESI⁺) m/z 987.25 (M+H)⁺.

TABLE 3 Compounds synthesized via Method 2, with the coupling of variousamines with acids in Step 1, followed by coupling with acids in Step 3.LCMS Step 1 Step 1 (ES+) Intermediate Intermediate Step 3 m/z Ex-# I-#Amine Acid Acid (M + H)⁺ HNMR (400 MHZ, DMSO-d6) δ 11 I-11 tert-butyl DC 936.0 11.13 (s, 1H), 10.35 (s, 1H), 9.05 (s, (2-(2-(2-(2- 1H), 8.56(t, J = 4 Hz, 3H), 8.42 (s, aminoethoxy)- 1H), 8.28 (d, J = 8.8 Hz, 1H),8.17 ethoxy)- (s, 1H), 8.14 (d, J = 7.6 Hz, 1H), ethoxy)ethyl) 8.03 (t,J = 5.6 Hz, 1H), 7.83-7.79 carbamate (m, 2H), 7.57 (d, J = 6 Hz, 1H),7.52 (CAS# (m, 2H), 7.41 (d, J = 8.4 Hz, 1H) 153086-78-3) 5.14-5.10 (m,1H), 4.79 (s, 2H), 3.70 (bs, 1H), 3.52-3.17 (m, 20H), 2.93- 2.87 (m,1H), 2.67-2.50 (m, 4H), 2.08-2.03 (m, 2H), 1.87 (d, J = 10 Hz, 2H), 1.76(d, J = 12.4 Hz, 2H), 1.46-1.30 (m, 4H), 0.96-0.93 (m, 2H), 0.58 (s, 2H)12 I-12 G I C 1056.8 10.37 (s, 1H), 9.05 (s, 1H), 8.99 (s, 1H),8.61-8.55 (m, 4H), 8.42 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.2- 8.13 (m,2H), 7.88 (d, J = 9.6 Hz, 1H), 7.75-7.65 (m, 2H), 7.57 (d, J = 5.6 Hz,1H), 7.50 (d, J = 9.2 Hz, 1H), 7.43-7.35 (m, 3H), 5.14 (bs, 1H),4.60-4.50 (m, 1H), 4.49-4.31 (m, 3H), 4.25-4.15 (m, 2H), 3.80- 3.60 (m,5H), 3.10-2.95 (m, 6H), 2.45 (s, 3H), 2.39-2.01 (m, 5H), 1.95-1.81 (m,3H), 1.80-1.65 (m, 5H), 1.55-1.15 (m, 24H), 0.94 (s, 10H), 0.58 (s, 2H)13^(c) I-13 G EN C 1090.7 10.35 (s, 1H), 9.05 (s, 1H), 8.99 (s, (M − H)⁺1H), 8.62-8.56 (m, 4H), 8.42 (s, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.15-8.13 (m, 2H), 7.81 (bs, 1H), 7.57- 7.55 (m, 1H), 7.51-7.49 (m, 1H),7.45-7.43 (m, 5H), 5.16 (bs, 1H), 4.58-4.56 (m, 1H), 4.46-4.35 (m, 4H),4.27-4.24 (m, 1H), 3.97 (s, 2H), 3.68-3.66 (m, 2H), 3.66-3.61 (m, 4H),3.58-3.54 (m, 4H), 3.53- 3.48 (m, 4H), 3.37-3.34 (m, 3H), 3.18-3.17 (m,2H), 2.67-2.60 (m, 1H), 2.44 (s, 3H), 2.08-2.06 (m, 2H), 1.87-1.85 (m,3H), 1.76-1.73 (m, 2H), 1.46-1.28 (m, 4H), 0.95 (s, 9H), 0.58 (s, 2H)14^(b) I-14 AB C G 1087.3 10.37 (s, 1H), 9.051-8.991 (m, 2H), 8.57 (s,4H), 8.42 (s, 1H), 8.27 (bs, 1H), 8.15 (bs, 1H), 7.90 (bs, 1H), 7.72(bs, 1H), 7.56-7.41 (m, 5H), 5.16 (bs, 1H), 4.55-4.23 (m, 4H), 3.65 (bs,3H), 3.0 (bs, 2H), 2.44- 2.33 (m, 4H), 2.12-2.04 (m, 3H), 1.92-1.87 (m,3H), 1.83-1.74 (m, 2H), 1.46-1.25 (m, 19H), 0.93 (s, 10H), 0.58 (s, 2H)15^(c) I-15 G 5-((tert- C 959.3 9.03 (s, 1H), 8.96 (s, 1H), 8.58-8.53butoxycarbonyl) (m, 4H), 8.40 (s, 1H), 8.25 (d, J = amino)pentanoic 4.8h, 1H), 8.13-8.11 (m, 1H), 7.87 acid (CAS# (d, J = 9.2 h, 1H), 7.71 (t,J = 5.2 27219-07-4) Hz, 1H), 7.55 (d, J = 5.6 Hz, 1H), 7.49 (d, J = 9.2Hz, 1H), 7.41-7.35 (m, 4H), 5.13 (s, 1H), 4.53 (d, J = 9.2 Hz, 1H), 4.44(m, 3H), 4.22-4.17 (m, 1H), 3.00 (d, J = 6 Hz, 2H), 2.65-2.58 (m, 1H),2.48 (s, 3H), 2.31-2.21 (m, 1H), 2.14-2.01 (m, 3H), 1.91-1.71 (m, 5H),1.46-1.26 (m, 8H), 0.92 (s, 11H), 0.56 (s, 2H) 16ª I-16 tert-butyl D 0863.7 12.80 (bs, 1H), 11.12 (s, 1H), 10.35 (2-(2-(2- (s, 1H), 9.03 (s,1H), 8.54-8.50 (m, aminoethoxy) 3H), 8.44 (s, 1H), 8.26 (d, J = 8.8ethoxy)ethyl) Hz, 1H), 8.11 (s, 1H), 8.01 (t, J = carbamate 5.2 Hz, 1H),7.82-7.77 (m, 2H), (CAS# 7.55-7.47 (m, 3H), 7.38 (d, J = 8.4153086-78-3) Hz, 1H), 5.12-5.08 ( m, 1H), 4.78 (s, 2H), 4.53-4.47 (m,1H), 3.50 (s, 3H), 3.46-3.32 (m, 4H), 3.32-3.29 (m, merged with waterpeak of DMSO, 3H), 3.22-3.17 (m, 2H), 2.91-2.85 (m, 2H), 2.65-2.48 (m,3H), 2.35-2.30 (m, 2H), 2.26-2.19 (m, 2H), 2.03-2.01 (m, 1H), 0.91 (s,2H), 0.54 (s, 2H) 17^(d) I-17 tert-butyl D AG 934.0 11.03 (s, 1H),9.07-9.04 (m, 2H), (2-(2-(2-(2- 8.67 (s, 1H), 8.60 (s, 1H), 8.55 (s,aminoethoxy) 1H), 8.40 (d, J = 7.6 Hz, 1H), 8.05- ethoxy)ethoxy) 8.02(m, 1H), 7.84-7.80 (m, 2H), ethyl)carbamate 7.68 (s, 1H), 7.51 (d, J =7.2 Hz, (CAS# 1H), 7.41 (d, J = 8.4 Hz, 1H), 5.15- 101187-40-0) 5.11 (m,1H), 4.80 (s, 2H), 3.73-3.71 (m, 1H), 3.53-3.48 (m, 11H), 3.46- 3.39 (m,3H), 3.38-3.35 (m, 1H), 3.20-3.18 (m, 2H), 2.95-2.86 (m, 1H), 2.68-2.63(m, 2H), 2.63-2.59 (m, 2H), 2.11-2.04 (m, 2H), 1.92- 1.89 (m, 2H),1.78-1.76 (m, 2H), 1.48-1.24 (m, 4H), 0.86 (d, J = 5.2 Hz, 2H), 0.58 (s,2H) 18 I-18 K D L 922.4 11.15 (s, 1H), 9.06 (dd, J = 1.6 and 12.8 Hz,2H), 8.67 (s, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H),8.08-8.01 (m, 1H), 7.87- 7.77 (m, 1H), 7.68 (s, 1H), 7.51 (d, J = 7.2Hz, 1H), 7.41 (d, J = 8.8 Hz, 1H), 5.16-5.11 (m, 1H), 4.81 (s, 2H),3.80-3.55 (m, 1H), 3.55-3.45 (m, 11H), 3.35-3.25 (m, 3H), 3.22 (d, J =6.4 Hz, 2H), 3.0-2.80 (m, 1H), 2.70-2.55 (m, 3H), 2.5-2.4 (m, 2H),2.10-2.0 (m, 1H), 1.95-1.7 (m, 4H), 1.60-1.45 (m, 1H), 1.4-1.3 (m, 2H),1.1-0.9 (m, 2H), 0.86 (d, J = 5.2 Hz, 2H), 0.57 (s, 2H) ^(a)HATU usedinstead of PyBOP as the coupling reagent in Step 1 and the reaction wasrun for 2 h at rt in DCM. In Step 2, the reaction was run for 3 h andthe product was triturated with MBTE. Step 3 was run for 3 h. ^(b)TFAwas used instead of HCl for the deprotection in Step 2 and was added at0° C., then the reaction was stirred at rt for 16 h. The producttriturated using n-pentanes. In Step 3, HATU was used instead of PyBOPas the coupling reagent and the final product was purified usingpreparative HPLC (0.1% ammonia in water/ACN). ^(c)HATU was used as thecoupling agent in Step 1 instead of PyBOP. In Step 2, the intermediatewas triturated using MTBE. ^(d)The final product was purified by silicagel column chromatography (7% MeOH—DCM).

Example 19 (Method 3):6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(1-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)piperidin-4-yl)nicotinamide,I-19

Step 1 Ethyl2-(4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)-piperidin-1-yl)acetate

A solution of6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinic acid(0.19 g, 0.58 mmol, Intermediate N), ethyl2-(4-aminopiperidin-1-yl)acetate hydrochloride (0.13 g, 0.58 mmol,Intermediate P), PyBOP (0.45 g, 0.87 mmol) and DIPEA (0.23 mL, 1.73mmol) in DMF (3 mL) was stirred at rt for 3 h. The reaction mixture wasthen transferred into ice water and the resulting mixture was extractedusing ethyl acetate (3×25 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure to and the crude product was purified using silica gelcolumn chromatography (50% EtOAc-Hexane) to give ethyl2-(4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)piperidin-1-yl)acetateas a light yellow solid (0.15 g, 39%). ¹H NMR (400 MHz, DMSO) δ 10.74(bs, 1H), 9.11 (s, 1H), 8.61-8.32 (m, 5H), 7.75-7.60 (m, 1H), 7.53 (d,J=8.8 Hz, 1H), 4.22-4.18 (m, 2H), 4.10-3.80 (m, 3H), 3.00-2.93 (m, 2H),2.67-250 (m, 2H), 2.08-1.65 (m, 4H), 1.26-1.15 (m, 4H), 0.95 (d, J=4.8Hz, 2H), 0.86-0.81 (m, 1H), 0.59 (s, 2H).

Step2—2-(4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)-piperidin-1-yl)aceticAcid

A solution of ethyl2-(4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)piperidin-1-yl)acetate (0.15 g, 0.31 mmol) and LiOH·H₂O(0.04 g, 0.93 mmol) in THF:MeOH (5 mL, 1:1) was stirred at rt for 5 h.The reaction mixture was then adjusted to pH of 4-5 using citric acidsolution. The solid precipitate was collected using filtration and thesolid was dried under vacuum to give2-(4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)piperidin-1-yl)aceticacid as a light yellow solid (0.065 g, 53%). LC-MS (ESI⁺) m/z 462.04(M+H)⁺.

Step3—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(1-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)piperidin-4-yl)nicotinamide

A solution of 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (0.06 g, 0.14mmol, synthesized via Method 4, Step 1-2 of Example 23),2-(4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)piperidin-1-yl)aceticacid (0.06 g, 0.14 mmol), PyBOP (0.11 g, 0.20 mmol) and DIPEA (0.05 mL,0.4 mmol) in DMF (3 mL) was stirred at rt for 2 h. The reaction mixturewas then transferred into ice water and resulting solid was filtered andpurified by preparative HPLC (0.1% formic acid in water/ACN)purification to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(1-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)piperidin-4-yl)nicotinamideI-19 as a light yellow solid (0.022 g, 19%). ¹H NMR (400 MHz, DMSO) δ11.10 (s, 1H), 9.67 (bs, 1H), 9.18 (s, 1H), 8.63-8.37 (m, 4H), 7.73 (bs,1H), 7.59-7.49 (m, 2H), 7.14 (d, J=8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H),6.59 (s, 1H), 5.06-5.02 (m, 1H), 3.86-3.71 (m, 1H), 3.60-3.54 (m, 6H),3.46-3.33 (m, 6H), 3.11-3.08 (m, 1H), 2.90-2.83 (m, 1H), 2.59-2.52 (m,2H), 2.16-1.98 (m, 5H), 1.89-1.82 (m, 3H), 0.94 (d, J=5.6 Hz, 2H), 0.58(s, 2H); LC-MS (ESI⁺) m/z (M+H)⁺=848.93

Example 20:6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(1-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)azetidin-3-yl)nicotinamide,I-20

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(1-(2-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)-2-oxoethyl)azetidin-3-yl)nicotinamidewas synthesized via Method 3 starting with Intermediate Q as the amineand Intermediate N as the acid in Step 1. Step 1 was started at 0° C.then allowed to warm to rt and stirred for 16 h. After the water quench,the product was extracted using 5% methanol in DCM and the product waspurified by silica gel column chromatography (8-9% MeOH-DCM). Step 2 wasrun at 0° C. for 2 h. Upon completion, the reaction mixture wasacidified with Dowex 50 Resin and the reaction mixture was filteredthrough celite and used directly in the subsequent step. In Step 3, theamine 4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione (synthesizedvia Method 4, Step 1-2 of Example 23) was coupled under the conditionsdescribed at 0° C. and stirred for 45 min. Purification by HPLC (5 mMammonium bicarbonate with 0.1% ammonia in water/ACN) gave the titleproduct I-20. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 10.38 (s, 1H),9.06 (s, 1H), 8.66 (d, J=6.8 Hz, 1H), 8.65-8.50 (m, 3H), 8.48 (s, 1H),8.28 (d, J=1.6 Hz, 1H), 7.70-7.55 (m, 3H), 7.51 (d, J=8.8 Hz, 1H), 7.14(d, J=8.4 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.69-6.59 (m, 1H), 5.06 (dd,J=12.8 Hz & 5.2 Hz, 1H), 4.55-4.45 (m, 1H), 3.70-3.60 (m, 3H), 3.59-3.40(m, 8H), 3.30-3.20 (m, 2H), 3.15-2.95 (m, 4H), 2.94-2.80 (m, 2H),2.65-2.55 (m, 1H), 2.10-1.95 (m, 2H), 1.80-1.70 (m, 1H), 0.94 (d, J=4.8Hz, 2H), 0.58 (s, 2H), LC-MS (ESI⁺) m/z 820.21 (M+H⁺).

Example 21:6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,3r)-3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamoyl)cyclobutyl)nicotinamide,I-21

6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,3r)-3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamoyl)cyclobutyl)nicotinamidewas synthesized via Method 3 starting with methyltrans-3-aminocyclobutane-1-carboxylate hydrochloride (CAS #74316-29-3)as the amine and Intermediate L as the acid in the first step. In Step1, HATU was used at the coupling reagent instead of PyBOP and thereaction mixture was stirred with acid Intermediate L for 30 min at 0°C. then the amine and base were added and the reaction was stirred at rtfor 1 h. After the aqueous work up, the solid precipitate was collectedand used directly in the subsequent reaction. Step 2 was run in a 1:1mixture of THF:water as the solvent. In Step 3 the starting materialamine used was Intermediate Z and the final product was purified usingsilica gel column chromatography (4% MeOH-DCM) to give the titlecompound I-21. ¹H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.07 (d, J=2 Hz,1H), 9.04 (d, J=2 Hz, 1H), 8.80 (d, J=7.2 Hz, 1H), 8.65 (d, J=11 Hz,2H), 8.56 (s, 1H), 7.87-7.84 (m, 1H), 7.68 (s 1H), 7.58 (t, J=7.2 Hz,1H), 7.14 (d, J=8.8 Hz, 1H), 7.03 (d, J=6.8 Hz, 1H), 6.61 (t, J=5.6 Hz,1H), 5.08-5.03 (m, 1H), 4.56-4.54 (m, 1H), 3.63-3.60 (m, 2H), 3.56-3.55(m, 13H), 3.47-3.42 (m, 2H), 3.24-3.20 (m, 2H), 2.93-2.85 (m, 2H),2.60-2.56 (m, 3H), 2.40-2.35 (m, 2H), 2.33-2.30 (m, 2H), 2.26-2.01 (m,1H), 0.87-0.83 (m, 2H), 0.58-0.56 (m, 2H). LC-MS (ESI⁺) m/z 892.8(M+H)⁺.

Example 22:6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,4r)-4-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamoyl)cyclohexyl)nicotinamide,I-22

6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,4r)-4-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)carbamoyl)cyclohexyl)nicotinamideI-22 was synthesized via Step 3 of Method 3 starting with acidIntermediate AG and amine Intermediate Z.

¹H NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 9.07 (s, 1H), 9.05 (s, 1H), 8.67(s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.42 (d, J=8 Hz, 1H), 7.81 (d,J=5.2 Hz, 1H), 7.68 (s, 1H), 7.59 (t, J=8 Hz, 1H), 7.17 (d, J=8.4 Hz,1H), 7.05 (d, J=7.2 Hz, 1H), 6.62 (s, 1H), 5.09-5.04 (m, 1H), 3.73-3.34(m, 19H), 3.35-3.25 (m, 2H), 3.03-3.02 (m, 2H), 2.94-2.86 (m, 2H),2.68-2.51 (m, 3H), 2.11-2.02 (m, 3H), 1.98-1.89 (m, 2H), 1.79-1.74 (m,4H), 1.46-1.33 (m, 4H), 0.87 (d, J=5.2 Hz, 2H), 0.57 (s, 1H). LC-MS(ESI⁺) m/z 921.5 (M+H)⁺.

Example 23 (Method 4):6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)-ethyl)carbamoyl)cyclohexyl)nicotinamide,I-23

Step 1—Tert-Butyl(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamate

To a stirred solution of2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (2.6 g, 9.4mmol, Intermediate R) and DABCO (1.4 g, 12.2 mmol) in DMF (15 mL) wasadded tert-butyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (2.8 g,11.3 mmol, CAS #153086-78-3) at rt. The resulting reaction mixtureheated to 80° C. and stirred for 2 h. The reaction mixture was thentransferred into ice water and the resulting mixture was extracted usingethyl acetate (3×50 mL). The combined organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the crude product was purified using silica gelcolumn chromatography (2% MeOH-DCM) to give tert-butyl(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamateas a yellow oil (0.6 g, 13%). LCMS (ESI⁺) m/z 505.5 (M+H)⁺.

Step2—4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride

To a stirred solution of tert-butyl(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamate(0.6 g, 1.2 mmol) in 1,4 dioxane (15 mL) was added 4 M HCl in dioxane(10 mL) at 0° C. The resulting reaction mixture was allowed to warm tort and stirred for 16 h. The reaction mixture was then evaporated undervacuum and the residue was triturated using MTBE to give4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride as yellow solid (0.48 g, 91%). LCMS (ESI⁺) m/z 405.4(M+H)⁺.

Step3—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)-cyclohexyl)nicotinamide

To a stirred suspension of(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylicacid (0.4 g, 0.9 mmol, Intermediate C) and4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (0.48 g, 1.07 mmol) in DMF (15 mL) was added DIPEA (0.8mL, 4.5 mmol) and PyBOP (0.7 g, 1.3 mmol) at rt. The resulting reactionmixture was stirred at rt for 1 h. The reaction mixture was thentransferred into ice water and the resulting solid was filtered off anddried reduced pressure. The crude product was purified using silica gelcolumn chromatography (6% MeOH-DCM) to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)-carbamoyl)cyclohexyl)nicotinamideI-23 as a yellow oil (0.41 g, 55%). ¹H NMR (400 MHz, DMSO) δ ppm 11.09(s, 1H), 10.34 (s, 1H), 9.03 (s, 1H), 8.55-8.54 (m, 3H), 8.39 (s, 1H),8.24 (d, J=8.8 Hz, 1H), 8.12 (d, J=7.6 Hz, 1H), 7.73-7.77 (m, 1H),7.57-7.53 (m, 2H), 7.49-7.47 (m, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.02 (d,J=7.2 Hz, 1H), 6.60 (m, 1H), 5.03-4.96 (m, 1H), 3.61-3.59 (m, 3H),3.55-3.54 (m, 2H), 3.51-3.50 (m, 2H), 3.47-3.44 (m, 2H), 3.39-3.36 (m,2H), 3.16-3.14 (m, 2H), 2.90-2.82 (m, 1H), 2.58-2.55 (m, 1H), 2.03 (m,2H), 1.84-1.82 (m, 2H), 1.73-1.71 (m, 2H), 1.42-1.38 (m, 2H), 1.35-1.33(m, 4H), 0.92-0.91 (m, 2H), 0.56 (s, 2H). LC-MS (ESI⁺) m/z 833.8 (M+H)⁺.

Example 24:6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide,I-24

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide I-24 was synthesized via Method 4 withIntermediate R as the fluorine and tert-butyl(14-amino-3,6,9,12-tetraoxatetradecyl)carbamate (CAS #811442-84-9) asthe amine in Step 1. Intermediate C was used as the acid in Step 3. ¹HNMR (400 MHz, DMSO) δ ppm 11.09 (s, 1H), 10.34 (s, 1H), 9.03 (s, 1H),8.55-8.54 (m, 3H), 8.40 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.11 (d, J=7.6Hz, 1H), 7.81-7.73 (m, 1H), 7.58-7.47 (m, 3H), 7.13 (d, J=8.8 Hz, 1H),7.02 (d, J=7.2 Hz, 1H), 6.60-6.58 (m, 1H), 4.96 (m, 1H), 3.68-3.61 (m,3H), 3.60-3.59 (m, 3H), 3.54-3.52 (m, 7H), 3.37-3.34 (m, 2H), 3.17-3.15(m, 2H), 3.17-3.15 (m, 2H), 2.91-2.82 (m, 1H), 2.65-2.58 (m, 1H),2.06-1.99 (m, 2H), 1.85-1.82 (m, 2H), 1.74-1.70 (m, 3H), 1.45-1.21 (m,4H), 0.92-0.84 (m, 2H), 0.56 (s, 2H). LC-MS (ESI⁺) m/z 922.2 (M+H)+

Example 25:6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide,I-25

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamideI-25 was synthesized via Method 4 using Intermediate R as the fluorineand tert-butyl (2-(2-aminoethoxy)ethyl)carbamate (CAS #127828-22-2) asthe amine in Step 1. The product of Step 2 was triturated with diethylether instead of MBTE. Intermediate C was used as the acid in Step 3 andthe final product was purified by HPLC (0.1% formic acid in water/ACN).¹H NMR (400 MHz, DMSO-d₆) δ 11.1 (s, 1H), 10.34 (s, 1H), 9.03 (s, 1H),8.56-8.54 (m, 3H), 8.40 (s, 1H), 8.25 (d, J=9.2 Hz, 1H), 8.15-8.05 (m,2H), 7.81-7.75 (m, 1H), 7.60-7.5 (m, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.14(d, J=8.4 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 6.59 (d, J=6.0 Hz, 1H), 5.04(dd, J=13.0 Hz & 5.4 Hz, 1H), 3.7-3.55 (m, 3H), 3.50-3.40 (m, 4H),3.25-3.15 (m, 2H), 2.90-2.80 (m, 1H), 2.55-2.65 (m, 2H), 2.10-1.95 (m,2H), 1.85-1.65 (m, 4H), 1.45-1.21 (m, 4H), 0.92 (d, J=5.2 Hz, 2H), 0.57(s, 2H); LC-MS (ESI⁺) m/z 789.7 (M+H)⁺.

Example 26:6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,3r)-3-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl) cyclobutyl)nicotinamide, I-26

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,3r)-3-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl) cyclobutyl)nicotinamide I-26 was synthesized via Method 4using Intermediate R as the fluorine and tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (CAS #153086-78-3) as theamine in Step 1. Intermediate O was used as the acid in Step 3. In Step3, HATU was used as the coupling reagent instead of PyBOP and thereaction was run at rt for 4 h. ¹H NMR (400 MHz, DMSO) δ 11.09 (s, 1H),10.36 (s, 1H), 9.03 (s, 1H), 8.55-8.50 (m, 3H), 8.44 (s, 1H), 8.26 (d,J=8.8 Hz, 1H), 7.79 (t, J=5.6 Hz, 1H), 7.58-7.54 (m, 2H), 7.49 (d, J 9.2Hz, 1H), 7.14 (d, J 8.4 Hz, 1H), 7.00 (d, J 7.2 Hz, 1H), 6.60 (s, 1H),5.06-5.02 (m, 1H), 4.51-4.49 (m, 1H), 3.62-3.32 (m, 10H), 3.20-3.14 (m,3H), 2.87-2.83 (m, 2H), 2.58-2.48 (m, 1H), 2.33-2.21 (m, 4H), 2.02-1.97(m, 2H), 1.21 (m, 1H), 0.92 (d, J=5.2 Hz, 2H), 0.55 (s, 2H). LC-MS(ESI⁺) m/z 805.68 (M+H)+

Example 27:6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1R,3R)-3-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclobutyl)nicotinamide, I-27

6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,3r)-3-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclobutyl)nicotinamide I-27 was synthesized via Method 4using Intermediate R as the fluorine and tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (CAS #153086-78-3) as theamine in Step 1.(1R,3R)-3-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)cyclobutane-1-carboxylicacid (synthesized via Steps 1-2 of Method 3 for Example 21) was used asthe acid in Step 3 which was run at rt for 2 h. The final compound waspurified by prep HPLC (0.1% formic acid in water/ACN). ¹H NMR (400 MHz,DMSO) δ 11.13 (s, 1H), 9.07 (d, J=2 Hz, 1H), 9.04 (d, J=2 Hz, 1H), 8.81(d, J=7.2 Hz, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 7.84 (t,J=6 Hz, 1H), 7.68 (s, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.16 (d, J=8.4 Hz,1H), 7.05 (d, J=7.2 Hz, 1H), 6.62 (t, J=5.6 Hz, 1H), 5.09-5.04 (m, 1H),4.56-4.52 (m, 1H), 3.64-3.50 (m, 6H), 3.48-3.35 (m, 5H), 3.24-3.20 (m,2H), 2.92-2.84 (m, 2H), 2.61-2.51 (m, 2H), 2.39-2.23 (m, 4H), 2.04-2.02(m, 1H). LC-MS (ESI⁺) m/z 804.5.

Example 29:6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide, I-29

6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide I-29 was synthesized via Method4 using Intermediate R as the fluorine and tert-butyl(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (CAS #153086-78-3) as theamine in Step 1. Intermediate AG was used as the acid in Step 3 whichwas run at rt for 2 h. The final product was purified using preparativeHPLC (0.1% formic acid in water/ACN). Characterization of the finalproduct: ¹H NMR (400 MHz, DMSO) δ 11.13 (s, 1H), 9.08 (dd, J₁=2 Hz,J₂=13 Hz, 1H), 8.67 (s, 2H), 8.60 (d, J=18.4 Hz, 1H), 8.42 (d, J=7.6 Hz,1H), 7.82-7.76 (m, 1H), 7.69 (s, 1H), 7.60 (t, J=7.6 Hz, 1H), 7.18 (d,J=8.4 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.63 (t, J=5.6 Hz, 1H), 5.10-5.05(m, 1H), 3.71-3.36 (m, 9H) 3.22-3.19 (m, 2H), 3.04-3.00 (m, 1H),2.94-2.85 (m, 1H), 2.62-2.51 (m, 2H), 2.11-1.91 (m, 2H), 1.88-1.78 (m,2H), 1.76-1.73 (m, 2H), 1.48-1.24 (m, 3H), 1.39-1.32 (m, 2H), 0.87-0.58(m, 2H). LC-MS (ESI⁺) m/z 832.78 (M+H)⁺.

Example 30 (Method 5):6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propyl)carbamoyl)cyclohexyl)nicotinamide, I-30

Step 1—Tert-Butyl(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propyl)carbamate

A solution of tert-butyl (3-(3-aminopropoxy)propyl)carbamate (0.36 g,1.55 mmol, Intermediate S),2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.47 g, 1.70mmol, Intermediate R) and DIPEA (0.4 mL, 2.3 mmol) in DMF (3 mL) wasstirred at 80° C. for 1 h. The reaction mixture was then transferredinto ice water and the resulting mixture was extracted using ethylacetate (3×20 mL). The combined organic layer was dried over anhydroussodium sulfate and filtered. The filtrate was evaporated under reducedpressure. The crude product was purified using silica gel columnchromatography (3% MeOH-DCM) to give tert-butyl(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propyl)carbamateas a yellow semi-solid (0.1 g, 13%). LC-MS (ESI⁺) m/z 489.5 (M+H)⁺.

Step2—4-((3-(3-aminopropoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dioneHydrochloride

To a solution of tert-butyl(3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propyl)carbamate(0.1 g, 0.2 mmol) in DCM (5 mL) was added 4N HCl in dioxane (2 mL) at 0°C. The reaction mixture was then allowed to come to rt and was stirredfor 3 h. The reaction mixture was then evaporated under vacuum to affordthe crude product which was triturated using MTBE (5 mL) to give4-((3-(3-aminopropoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride as a yellow solid (0.06 g, 69%). LC-MS (ESI⁺) m/z 389.4(M+H)⁺.

Step3—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propyl)carbamoyl)cyclohexyl)nicotinamide

A solution of4-((3-(3-aminopropoxy)propyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dionehydrochloride (0.06 g, 0.14 mmol),(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotineamido)cyclohexane-1-carboxylicacid (0.063 g, 0.14 mmol, Intermediate C), PyBOP (0.11 g, 0.21 mmol) andDIPEA (0.1 mL, 0.42 mmol) in DMF (3 mL) was stirred at rt for 2 h. Thereaction mixture was then poured in ice water mixture (50 mL) and thesolid precipitated was filtered. The crude solid was then purified byprep HPLC (0.1% formic acid in water/ACN) to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((3-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)propoxy)propyl)carbamoyl) cyclohexyl)nicotinamide I-30 as a yellow solid (0.018g, 16%). ¹H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 10.36 (s, 1H), 9.05 (s,1H), 8.57 (d, J=5.2 Hz, 2H), 8.42 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.15(d, J=4.4 Hz, 1H), 7.73-7.71 (m, 1H), 7.59-7.49 (m, 3H), 7.12 (d, J=8.8Hz, 2H), 7.04 (d, J=7.2 Hz, 1H), 6.75-6.65 (m, 1H), 5.14-5.10 (m, 1H),3.60-3.70 (m, 2H), 3.45 (t, J=5.6 Hz, 2H), 3.39-3.34 (m, 3H), 3.11-3.09(m, 2H), 3.00-2.80 (m, 2H), 2.67-2.50 (m, 4H), 2.33 (s, 1H), 2.10-2.00(m, 2H), 2.05-1.63 (m, 7H), 1.45-1.25 (m, 4H), 0.95 (d, J=4.8 Hz, 2H),0.58 (s, 2H). LC-MS (ESI⁺) m/z 817.8 (M+H)⁺.

TABLE 4 Compounds synthesized via Method 5 with the addition of variousamines to fluoride Intermediate R in Step 1, followed coupling withvarious acids in Step 3 LCMS Step 1 (ES+) Intermediate Step 3 m/z Ex-#I-# Amine Acid (M + H)⁺ HNMR (400 MHz, DMSO-d6) δ 31 I-31 H N 792.411.13 (s, 1H), 10.38 (s, 1H), 9.06 (s, 1H), 8.58-8.55 (m, 4H), 8.48 (s,1H), 8.29 (d, J = 9.2 Hz, 1H), 7.61- 7.50 (m, 3H), 7.33-7.32 (m, 1H),7.17 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.64 (t, J = 5.6 Hz,1H), 5.10-5.05 (m, 1H), 4.51-4.41 (m, 2H), 3.66-3.41 (m, 13H), 2.68-2.57(m, 2H), 2.37-2.34 (m, 1H), 2.20- 2.13 (m, 2H), 2.06-2.20 (m, 3H), 1.24(m, 1H), 0.95 (d, J = 4.8 Hz, 2H), 0.58 (s, 2H) 32 I-32 W L 819.8 11.11(s, 1H), 9.08 (d, J = 2 Hz, 1H), 9.04 (d, J = 2 Hz, 1H), 8.68 (s, 1H),8.63 (s, 1H), 8.59 (s, 1H), 8.43 (d, J = 7.6 Hz, 1H), 7.74 (s, 1 Hz,1H), 7.61-7.57 (m, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 7.2 Hz,1H), 6.62 (s, 1H), 5.07-5.04 (m, 1H), 3.71-3.68 (m, 1H), 3.65-3.58 (m,2H), 3.57-2.53 (m, 11H), 3.21-3.19 (m, 2H), 2.89-2.84 (m, 1H), 2.60-2.57 (m, 2H), 2.05-2.01 (m, 1H), 1.87-1.85 (m, 2H), 1.78-1.75 (m, 2H),1.47-1.45 (m, 1H), 1.34-1.27 (m, 2H), 1.03-0.97 (m, 2H), 0.87- 0.84 (m,2H), 0.57 (s, 2H) 33 I-33 Y L 907.8 11.11 (s, 1H), 9.08 (s, 1H), 9.04(s, 1H), 9.89-9.59 (m, 3H), 8.46 (d, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.58(t, J = 7.6 Hz, 1H), 7.15-7.03 (m, 2H), 6.61 (s, 1H), 5.06 (d, J = 7.6Hz, 1H), 3.70-3.56 (m, 9H), 3.50-3.20 (m, 12H), 2.92-2.85 (m, 1H),2.08-2.02 (m, 2H), 1.88-1.76 (m, 4H), 1.48- 1.23 (m, 5H), 1.09-0.98 (m,2H), 0.88-0.86 (m, 2H), 0.58 (s, 3H) 34 I-34 H N 791.7 11.13 (s, 1H),9.07 (dd, J₁ = 2 Hz, J₂ = 2 Hz, 2H), 8.81 (d, J = 6.8 Hz, 2H), 8.66 (s,1H), 8.64 (s, 1H), 8.57 (s, 1H), 7.68 (s, 1H), 8.14 (t, J = 7.2 Hz, 1H),7.16 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.25 (t, J = 6 Hz,1H), 5.08-5.04 (m, 1H), 4.48- 4.42 (m, 1H) 3.68-3.45 (m, 12H), 2.93-2.84(m, 1H), 2.60-2.50 (m, 4H), 2.39-2.33 (m, 1H), 2.21-2.01 (m, 3H),0.87-0.82 (m, 2H), 0.57- 0.53 (m, 2H) 35 I-35 U L 805.7 11.13 (s, 1H),9.07 (d, J = 12 Hz, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.50(d, J = 8 Hz, 1H), 7.68 (s, 1H), 7.59 (t, J = 8 Hz, 1H), 7.15 (d, J = 12Hz, 1H), 7.05 (d, J = 4 Hz, 1H), 6.63 (s, 1H), 5.07 (d, J = 8 Hz, 1H),4.25 (d, J = 4 Hz, 1H), 3.65- 3.49 (m, 13H), 3.29-3.28 (m, 2H),2.94-2.87 (m, 1H), 2.62-2.56 (m, 3H), 2.34 (d, J = 8 Hz, 1H), 2.06- 1.95(m, 2H), 1.83 (s, 1H), 1.70-1.58 (m, 3H), 1.25 (s, 1H), 0.87-0.84 (m,2H), 0.58 (s, 2H)  36^(a) I-36 ES L 878.9 11.03 (s, 1H), 9.07 (d, J = 4Hz, 1H), 9.04 (d, J = 4 Hz, 1H), 8.83 (d, J = 8 Hz, 1H), 8.67 (d, J = 8Hz, 2H), 8.59 (s, 1H), 7.69 (s, 1H), 7.59 (t, J = 8 Hz, 1H), 7.15 (d, J= 8 Hz, 1H), 7.04 (d, J = 4 Hz, 1H), 6.63-6.61 (m, 1H), 5.09-5.05 (m,1H), 4.50-4.44 (m, 1H), 3.64-3.62 (m, 2H), 3.57-3.48 (m, 18H), 2.94-2.85(m, 1H), 2.62- 2.52 (m, 3H), 2.42-2.35 (m, 1H), 2.24-22.19 (m, 2H),2.11-2.03 (m, 3H), 0.89-0.84 (m, 2H), 0.57 (s, 2H) 37 I-37 EP(1R,3R)-3-(6- 818.7 11.13 (s, 1H), 9.09-9.05 (m, 2H), (5-cyano-1H- 8.84(t, J = 7.2 Hz, 1H), 868 (d, J = pyrazolo[3,4- 7.6 Hz, 2H), 8.56 (s,1H), 7.69 (d, J = b]pyridin-1-yl)- 2.4 Hz, 1H), 7.59-7.57 (m, 1H),4-(cyclopropyl- 7.15 (t, J = 9.2 Hz, 1H), 7.04 (t, J = amino)- 7.2 Hz,1H), 6.65-6.60 (m, 1H), nicotinamido)- 2.10-5.04 (m, 1H), 4.42-4.35 (m,cyclobutane-1- 1H), 3.66-3.28 (m, 11H), 2.93-2.85 carboxylic acid (m,4H), 2.69-2.35 (m, 5H), 2.33- (synthesized via 2.26 (m, 2H), 2.06-2.02(m, 1H), Steps 1-2 of 0.88-0.84 (m, 2H), 0.59 (d, J = 6.8 Method 3 forHz, 2H) Example 21) 38 I-38 V AG 934.9 11.11 (s, 1H), 9.08-9.03 (m, 2H),8.67 (s, 1H), 8.60 (s, 1H), 8.53 (s, 1H), 8.45-8.40 (m, 1H), 7.68 (s,1H), 7.61-7.54 (m, 1H), 7.17-7.11 (m, 1H), 7.06-7.02 (m, 1H), 6.58-6.55(m, 1H), 5.05-5.02 (m, 1H), 3.72- 3.65 (m, 1H), 3.63-3.61 (m, 2H),3.60-3.54 (m, 9H), 4.46-3.43 (m, 6H), 3.06 (s, 2H), 2.93-2.86 (m, 2H),2.68-2.57 (m, 4H), 2.51-2.34 (m, 3H), 2.05-2.03 (m, 1H), 2.02-1.92 (m,2H), 1.76-1.74 (m, 2H), 1.48- 1.42 (m , 4H), 0.97-0.85 (m, 2H), 0.57 (m,2H) 39 I-39 V (1R,3R)-3-(6- 906.8 11.12 (s, 1H), 9.07-9.04 (m, 2H),(5-cyano-1H- 8.87-8.84 (m, 1H), 8.68-8.67 (m, pyrazolo[3,4- 2H), 8.57(s, 1H), 7.70 (s, 1H), 7.58- b]pyridin-1-yl)- 7.56 (m, 1H), 7.16-7.12(m, 1 Hz, 4-(cyclopropyl- 1H), 7.05-7.02 (m, 1H), 6.61-6.59 amino)- (m,1H), 5.08-5.04 (m, 1H), 4.42- nicotinamido)- 4.40 (m, 1H), 3.64-3.62 (m,2H), cyclobutane-1- 3.61-3.54 (m, 11H), 3.53-3.50 (m, carboxylic acid3H), 2.91 (s, 2H), 2.86 (s, 1H), 2.68- (synthesized via 2.57 (m, 4H),2.51-2.46 (m, 3H), Step 1-2 of 2.34-2.29 (m, 3H), 2.05-0.02 (m, Method 3for 1H), 0.87-0.85 (m, 2H), 0.57 (s, 2H) Example 21) *Step 1 was run at80-90° C. for 1-1.5 h. The intermediate of Step 2 could also betriturated with similar solvents to MBTE, such as diethyl ether. Thefinal product of Step 3 was often purified by silica gel columnchromatography (10% MeOH-DCM) first, then preparative HPLC (0.1% formicacid in water/ACN). ^(a)Step 2 was run for 16 h at rt and theintermediate was not triturated.

Example 40 (Method 6):6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)nicotinamide, I-40

Step 1—Tert-Butyl(2-(2-(2-((1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)-N-methylcyclohexane-1-carboxamido)ethoxy)ethoxy)ethyl)carbamate

A solution of(1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)cyclohexane-1-carboxylic acid (0.7 g, 1.57 mmol,Intermediate C),tert-butyl(2-(2-(2-(methylamino)ethoxy)ethoxy)ethyl)carbamate (0.42 g,1.57 mmol, Intermediate AC), PyBOP (1.23 g, 2.40 mmol) and DIPEA (0.7mL, 2.5 mmol) in DMF (10 mL) was stirred at rt for 2 h. The reactionmixture was then transferred into ice water and the resulting mixturewas extracted using ethyl acetate (3×30 mL). The combined organic layerwas dried over anhydrous sodium sulfate and filtered. The filtrate wasevaporated under reduced pressure and the crude product which waspurified using silica gel column chromatography (5% MeOH-DCM) to givetert-butyl(2-(2-(2-((1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)-N-methylcyclohexane-1-carboxamido)ethoxy)ethoxy)ethyl)carbamate as a yellow solid (0.3 g, 24%)

LC-MS (ESI⁺) m/z 494.5 (M+H)⁺.

Step2—6-((1,6-naphthyridin-2-yl)amino)-N-((1R,4R)-4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)-4-(cyclopropylamino)nicotinamidehydrochloride

To the solution of tert-butyl(2-(2-(2-((1R,4R)-4-(6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)nicotinamido)-N-methylcyclohexane-1-carboxamido)ethoxy)ethoxy)ethyl)-carbamate(0.3 g, 0.43 mmol) in DCM (3 mL) was added 4N HCl in dioxane (2 mL) at0° C. The reaction mixture was allowed to warm to rt and stirred for 3h. The reaction mixture was then evaporated under vacuum to afford thecrude product which was triturated using MTBE (5 mL) to give6-((1,6-naphthyridin-2-yl)amino)-N-((1R,4R)-4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)-(methyl)carbamoyl)cyclohexyl)-4-(cyclopropylamino)nicotinamidehydrochloride as a light yellow solid (0.25 g, 97%). LC-MS (ESI⁺) m/z591.4 (M+H)⁺.

Step3—6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)nicotinamide

A solution of6-((1,6-naphthyridin-2-yl)amino)-N-((1R,4R)-4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)-4-(cyclopropylamino)nicotinamidehydrochloride (0.25 g, 0.42 mmol),2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (0.13 g, 0.46mmol, Intermediate R) and DIPEA (0.22 mL, 1.26 mmol) in DMF (2 mL) washeated at 90° C. for 1 h. The reaction mixture was then transferred intoice water and the resulting mixture was extracted using ethyl acetate(3×20 mL). The combined organic layer was dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated under reduced pressureand the crude product was purified using preparative HPLC (0.1% formicacid in water/ACN) to give6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1R,4R)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)nicotinamide I-40 as yellow solid (0.01 g, 5%). ¹HNMR (400 MHz, DMSO) δ 11.11 (s, 1H), 10.35 (s, 1H), 9.05 (s, 1H),8.57-8.56 (m, 3H), 8.42 (d, J=5.2 Hz, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.16(s, 1H), 8.14-8.11 (m, 1H), 7.61-7.50 (m, 3H), 7.16-7.13 (m, 1H),7.06-7.03 (m, 1H), 6.62 (t, J=5.6 Hz, 1H), 5.03 (t, J=8.4 Hz, 1H),3.64-3.34 (m, 11H), 3.03 (s, 2H), 2.85 (s, 2H), 2.67-2.50 (m, 3H), 2.04(bs, 1H), 1.90-1.80 (m, 2H), 1.46-1.38 (m, 4H), 0.95 (t, J=5.2 Hz, 1H),0.57 (s, 1H). LC-MS (ESI⁺) m/z 848 (M+H)⁺.

Example 41:6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-((5-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)methyl)pyridin-2-yl)methoxy)ethyl)carbamoyl)cyclohexyl)nicotinamide,I-41

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-((5-((2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)methyl)pyridin-2-yl)methoxy)ethyl)carbamoyl)cyclohexyl)nicotinamideI-41 was synthesized via Method 6 using Intermediate AF as the amine andIntermediate C as the acid in Step 1. In Step 3, Intermediate R was usedas the fluorine and the reaction was run for 2 h at 90° C. The finalproduct was purified first by silica gel column chromatography (15%MeOH-DCM) followed by preparative HPLC (0.1% formic acid in water/ACN).Characterization of the final product: ¹H NMR (400 MHz, DMSO-d₆) δ 11.13(s, 1H), 10.37 (s, 1H) 9.06 (s, 1H), 8.60-8.55 (m, 3H), 8.49 (s, 1H),8.43 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.15 (d, J 8.0 Hz, 1H), 7.91 (t,J=5.2 Hz, 1H), 7.76 (d, J=6.4 Hz, 1H), 7.61-7.55 (m, 2H), 7.52 (d, J=9.2Hz, 1H), 7.43 (d, J 7.6 Hz, 1H), 7.17 (d, J 8.4 Hz, 1H), 7.05 (d, J 7.2Hz, 1H), 6.70-6.60 (m, 1H), 5.11-5.06 (m, 1H), 4.65-4.50 (m, 4H),3.75-3.65 (m, 3H), 3.60-3.50 (m, 4H), 3.33-3.25 (m, 2H), 3.30-2.80 (m,2H), 2.70-2.60 (m, 2H), 2.22-2.00 (m, 2H), 1.95-1.85 (m, 2H), 1.80-1.60(m, 2H), 1.50-1.25 (m, 4H), 0.95 (d, J=5.2 Hz, 2H), 0.59 (s, 2H), LC-MS(ESI⁺) m/z 909.8 (M+H)⁺.

Example 42:6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)nicotinamide, I-42

6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)nicotinamide I-42 was synthesized viaMethod 6 using Intermediate AC as the amine and Intermediate AG as theacid in Step 1. In Step 3, Intermediate R was used as the fluorine.Characterization of the final product: ¹H NMR (400 MHz, DMSO) δ 11.13(s, 1H), 9.07 (s, 1H), 9.04 (d, J=2 Hz, 1H), 8.67 (s, 1H), 8.60 (t,J=4.4 Hz, 1H), 8.53 (s, 1H), 8.45-8.39 (m, 1H), 7.68 (s, 1H), 7.62-7.57(m, 1H), 7.18-7.14 (m, 1H), 7.07-7.03 (m, 1H), 6.63 (bs, 1H), 5.10-5.05(m, 1H), 3.70 (bs, 1H), 3.63-3.39 (m, 11H), 3.04 (s, 2H), 2.93-2.85 (m,1H), 2.80 (s, 2H), 2.68-2.51 (m, 4H), 2.09-2.04 (m, 1H), 1.92-1.85 (m,2H), 1.74-1.72 (m, 2H), 1.47-1.40 (m, 4H), 0.87 (d, J=5.2 Hz, 1H), 0.58(s, 2H). LC-MS (ESI⁺) m/z 846.2

Example 43:6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)nicotinamide, I-43

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-(1-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)acetyl)piperidin-4-yl)nicotinamide I-43 was synthesized via Method 6 usingIntermediate EO as the amine and2,2-dimethyl-4-oxo-3,8,11,14-tetraoxa-5-azahexadecan-16-oic acid (CAS#462100-06-7) as the acid in Step 1. In Step 3, Intermediate R was usedas the fluorine. Characterization of the final product: ¹H NMR (400 MHz,DMSO) δ 11.11 (s, 1H), 10.36 (s, 1H), 9.05 (s, 1H), 8.57-8.54 (m, 3H),8.43 (s, 1H), 8.28 (d, J=9.2 Hz, 1H), 8.22-8.16 (m, 1H), 7.59-7.49 (m,3H), 7.14 (d, J=8.4 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 6.61 (t, J=5.6 Hz,1H), 5.08-5.03 (m, 1H), 4.30-4.27 (m, 1H), 4.19-4.08 (m, 2H), 3.99-3.97(m, 1H), 3.83-3.80 (m, 1H), 3.83-3.61 (m, 2H), 3.57-3.33 (m, 8H),3.10-3.00 (m, 1H), 2.88-2.85 (m, 1H), 2.70-2.50 (m, 5H), 2.04-2.01 (m,1H), 1.90-1.75 (m, 2H), 1.55-1.30 (m, 2H), 0.95 (d, J=5.2 Hz, 1H), 0.58(s, 1H). LC-MS (ESI⁺) m/z 849.4 (M+H)⁺.

Example 44:6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1r,4r)-4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclohexyl)nicotinamide, I-44

6-((1,6-naphthyridin-2-yl)amino)-4-(cyclopropylamino)-N-((1r,3r)-3-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)(methyl)carbamoyl)cyclobutyl)nicotinamide I-44 was synthesized via Method 6using Intermediate AC as the amine and Intermediate O as the acid inStep 1. In Step 3, Intermediate R was used as the fluorine.Characterization of the final product: ¹H NMR (400 MHz, DMSO) δ 11.10(s, 1H), 10.36 (d, J=4 Hz, 1H), 9.05 (s, 1H), 8.57-8.56 (m, 3H), 8.47(s, 1H), 8.28 (d, J=9.2 Hz, 1H), 7.60-7.50 (m, 3H), 7.16 (t, J=8.4 Hz,1H), 7.05-7.02 (m, 1H), 6.63-6.60 (m, 1H), 5.08-5.03 (m, 1H), 4.38-4.30(m, 1H), 3.64-3.44 (m, 12H), 2.91 (s, 3H), 2.67-2.54 (m, 3H), 251-2.50(m, 3H), 2.42-2.24 (m, 3H), 2.04-2.01 (m, 1H), 0.94 (t, J=6.4 Hz, 1H),0.57 (t, J=6.4 Hz, 1H). LC-MS (ESI⁺) m/z 818.92 (M+H)⁺.

Example 45:6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1R,4R)-4-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,9,12-trioxa-6-azatetradecyl)carbamoyl)cyclohexyl)nicotinamide,I-45

6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-((1R,4R)-4-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,9,12-trioxa-6-azatetradecyl)carbamoyl)cyclohexyl)nicotinamideI-45 was prepared via Method 6 using Intermediate ER as the amine andIntermediate AG as the acid in Step 1. In Step 2, the BOC intermediatewas deprotected using TFA at rt in DCM for 2 h. In Step 3, IntermediateR was used as the fluorine and the reaction was run at 80° C. for 2 h.Characterization of the final product: ¹H NMR (400 MHz, DMSO-d₆) δ 11.05(s, 1H), 9.08-9.04 (m, 2H), 8.67 (s, 1H), 8.61 (s, 1H), 8.56 (s, 1H),8.42 (d, J=7.2 Hz, 1H), 7.86-7.83 (m, 1H), 7.69 (s, 1H), 7.61-7.57 (m,1H), 7.17-7.15 (m, 1H), 7.06-7.04 (m, 1H), 6.64-6.61 (m, 1H), 5.09-5.05(m, 1H), 3.74-3.72 (m, 2H), 3.65-3.63 (m, 5H), 3.60-3.59 (m, 6H),3.41-3.38 (m, 4H), 3.23-3.20 (m, 2H), 2.94-2.90 (m, 1H), 2.76-2.74 (m,4H), 2.69-2.62 (m, 2H), 2.15-2.09 (m, 2H), 2.03-1.93 (m, 2H), 1.90-1.79(m, 2H), 1.50-1.31 (m, 5H), 0.89-0.86 (m, 2H), 0.58 (s, 2H), LC-MS(ESI⁺) m/z 919.09 (M+H)⁺.

Example 46 (Method 7):6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-[3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]-2-fluoro-propyl]pyridine-3-carboxamide,I-46

Step 1—Tert-ButylN-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-propoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethoxy]ethyl]carbamate (200mg, 617 umol, Intermediate A1),6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxylic acid (268 mg, 617 umol, Intermediate L, as the TFAsalt) and DIPEA (398 mg, 3.08 mmol) in DMF (3 mL) was added HATU (281mg, 740 umol). The mixture was stirred at rt for 1 h. On completion, thereaction mixture was diluted with H₂O (30 mL), extracted with EA (3×20mL), dried with Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% NH₃H₂O) to give the title compound (82.0mg, 21% yield) as a yellow oil. LC-MS (ESI⁺) m/z 627.4 (M+H)⁺.

Step2—N-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-2-fluoro-propyl]-6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxamide

To a solution of tert-butylN-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-propoxy]ethoxy]ethoxy]ethyl]carbamate(90.0 mg, 144 umol) in DCM (2 mL) was added HCl in dioxane (4 M, 2 mL).The mixture was stirred at rt for 15 minutes. On completion, thereaction mixture was concentrated in vacuo to give the title compound(75.0 mg, 93% yield) as a yellow oil. LC-MS (ESI⁺) m/z 527.4 (M+H)⁺.

Step3—6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-[3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]-2-fluoro-propyl]pyridine-3-carboxamide

To a solution ofN-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]-2-fluoro-propyl]-6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxamide(75.0 mg, 133 umol, HCl salt) in dioxane (4 mL) was added DIPEA (172 mg,1.33 mmol) and 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione(36.8 mg, 133 umol, Intermediate R). The mixture was heated to 115° C.and stirred for 60 h. On completion, the mixture was concentrated invacuo. The residue was further purification by pre-HPLC (column: BostonGreen ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B %:32%-62%, 10 min) to give the title compound I-46 (42.0 mg, 38% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.16-11.08 (m, 1H), 9.09-9.06(m, 1H), 9.05-9.02 (m, 1H), 8.85 (t, J=5.2 Hz, 1H), 8.68 (s, 1H), 8.64(s, 1H), 8.59-8.54 (m, 1H), 7.71 (s, 1H), 7.59-7.53 (m, 1H), 7.15 (d,J=8.8 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 6.63-6.59 (m, 1H), 5.09-5.02 (m,1H), 4.87-4.70 (m, 1H), 3.71-3.65 (m, 1H), 3.64-3.61 (m, 2H), 3.60-3.52(m, 10H), 3.50-3.46 (m, 2H), 2.91-2.83 (m, 1H), 2.63-2.56 (m, 2H),2.56-2.54 (m, 2H), 2.07-1.99 (m, 1H), 0.90-0.83 (m, 2H), 0.57-0.55 (m,2H); LC-MS (ESI⁺) m/z 783.2 (M+H).

TABLE 5 Compounds synthesized via Method 7, with the coupling of aminesand acids in Step 1, followed by the addition to fluoride Intermediate Rin Step 3 LCMS (ES+) Intermediate Intermediate m/z Ex-# I-# Amine Acid(M + H)⁺ HNMR (400 MHz, DMSO-d6) δ  47^(c) I-47 BR N 984.6 11.11 (s,1H), 10.37 (s, 1H), 9.05 (s, 1H), 8.58-8.55 (m, 4H), 8.46 (s, 1H), 8.28(s, 1H), 7.61-7.55 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 8.4Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.05 (dd, J= 5.6, 12.8 Hz, 1H), 4.83-4.69 (m, 1H), 3.50- 3.42 (m, 22H), 2.96-2.78(m, 2H), 2.61 (s, 2H), 2.55 (d, J = 9.2 Hz, 2H), 2.46 (s, 2H), 2.44-2.41(m, 4H), 2.39-2.35 (m, 4H), 2.05-1.90 (m, 2H), 1.18-1.06 (m, 1H),0.96-0.92 (m, 2H), 0.60-0.57 (m, 2H) 48 I-48 AK N 872.5 11.10 (s, 1H),10.36 (s, 1H), 9.05 (s, 1H), 8.59-8.55 (m, 3H), 8.46 (s, 1H), 8.26 (d, J= 9.2 Hz, 1H), 8.16 (s, 1H), 7.59-7.53 (m, 2H), 7.50 (d, J = 8.8 Hz,1H), 7.12 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.59 (t, J =5.6 Hz, 1H), 5.11-5.01 (m, 1H), 4.85-4.66 (m, 1H), 3.72-3.65 (m, 1H),3.65-3.51 (m, 14H), 3.49-3.40 (m, 8H), 2.93-2.80 (m, 1H), 2.65-2.55 (m,2H), 2.55-2.51 (m, 2H), 2.07-1.96 (m, 1H), 0.97-0.91 (m, 2H), 0.61-0.55(m, 2H)  49^(c, d) I-49 AI N 784.1 11.11 (s, 1H), 10.38 (s, 1H), 9.05(s, 1H), 8.60-8.53 (m, 4H), 8.46 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H),7.60-7.53 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H),7.02 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 5.6,12.8 Hz, 1H), 4.83-4.67 (m, 1H), 3.72-3.58 (m, 8H), 3.49-3.42 (m, 6H),3.01-2.75 (m, 2H), 2.59-2.54 (m, 4H), 2.07-1.97 (m, 1H), 0.97-0.91 (m,2H), 0.59-0.56 (m, 2H)  50^(d) I-50 BA N 828.2 11.11 (s, 1H), 10.37 (s,1H), 9.05 (s, 1H), 8.60-8.52 (m, 4H), 8.45 (s, 1H), 8.27 (d, J = 8.8 Hz,1H), 7.60-7.53 (m, 2H), 7.49 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8 Hz,1H), 7.02 (d, J = 7.2 Hz, 1H), 6.59 (s, 1H), 5.05 (dd, J = 5.2, 12.6 Hz,1H), 4.84-4.66 (m, 1H), 3.70-3.53 (m, 18H), 3.05-2.71 (m, 2H), 2.64-2.57(m, 2H), 2.57-2.53 (m, 2H), 2.07-1.97 (m, 1H), 0.97-0.90(m, 2H),0.62-0.54 (m, 2H) 51 I-51 BP N 916.5 11.1 (s, 1H), 10.3 (s, 1H), 9.05(s, 1H), 8.59-8.54 (m, 4H), 8.47 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H),7.59-7.55 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H),7.03 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.06 (dd, J = 5.2,8.8 Hz, 1H), 4.84-4.69 (m, 1H), 3.70-3.69 (m, 1H), 3.68-3.53 (m, 26H),2.94-2.83 (m, 1H), 2.61 (s, 2H), 2.58-2.53 (m, 2H), 2.06-1.99 (m, 1H),0.95-0.94 (m, 2H), 0.61-0.58 (m, 2H) 52 I-52 AK BY 877.3 11.1 (s, 1H),9.38 (s, 1H), 9.15 (s, 1H), 8.67 (d, J = 2.0 Hz, 1H), 8.46 (t, J = 5.6Hz, 1H), 8.30 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.66-7.51 (m, 2H), 7.13(d, J = 8.8 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H),6.41 (s, 1H), 5.06 (dd, J = 5.6, 6.4 Hz, 1H), 4.84- 4.65 (m, 1H),3.55-3.44 (m, 22H), 2.94- 2.82 (m, 1H), 2.60-2.56 (m, 1H), 2.55- 2.52(m, 2H), 2.47-2.42 (m, 2H), 2.06- 1.98 (m, 1H), 0.83-0.74 (m, 2H), 0.53-0.48 (m, 2H) 53 I-53 tert-butyl N- CN 1012.0^(a) 11.10 (s, 1H), 11.01(s, 1H), 9.03 (d, J = [2-[2-[2-[2-(2- 4.8 Hz, 2H), 8.65 (t, J = 5.2 Hz,1H), aminoethoxy) 8.26 (d, J = 5.2 Hz, 1H), 8.18-8.00 (m, ethoxy]- 5H),7.78 (s, 1H), 7.70 (t, J = 6.8 Hz, ethoxy]ethoxy]- 1H), 7.61-7.53 (m,1H), 7.27 (s, 1H), ethyl]carbamate 7.18 (d, J = 6.0 Hz, 1H), 7.12 (d, J= 8.4 (CAS# Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.58 01187-40-0) (t, J =6.0 Hz, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H), 4.31-4.19 (m, 2H), 3.69-3.46 (m, 20H), 2.95-2.82 (m, 1H), 2.63-2.57 (m, 2H), 2.10-1.97 (m, 1H) 54^(b) I-54 AI BY 789.1 11.12 (s, 1H), 9.39 (s, 1H), 9.16 (s, 1H), 8.68(s, 1H), 8.46 (t, J = 5.6 Hz, 1H), 8.40 (s, 1H), 8.18 (s, 1H), 7.95 (d,J = 8.8 Hz, 1H), 7.64-7.53 (m, 2H), 7.13 (d, J = 8.8 Hz, 1H), 7.04 (d, J= 7.2 Hz, 1H), 6.65-6.56 (m, 1H), 6.41 (s, 1H), 5.06 (dd, J = 5.2, 12.8Hz, 1H), 4.84- 4.62 (m, 1H), 3.69-3.55 (m, 16H), 2.95- 2.82 (m, 1H),2.59-2.44 (m, 3H), 2.07- 1.98 (m, 1H), 0.79-0.77 (m, 2H), 0.51- 0.49(m,2H) 55 I-55 BS N 869.3 11.10 (s, 1H), 10.36 (s, 1H), 9.05 (s, 1H), 8.64(t, J = 5.2 Hz, 1H), 8.59-8.55 (m, 3H), 8.47 (s, 1H), 8.27 (d, J = 8.8Hz, 1H), 7.59-7.53 (m, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.05 (dd, J= 5.2, 12.8 Hz, 1H), 4.61-4.45 (m, 1H), 3.90 (s, 2H), 3.84-3.77 (m, 1H),3.74-3.59 (m, 10H), 3.30-3.26 (m, 2H), 2.94-2.83 (m, 1H), 2.65-2.56(m,2H), 2.50-2.41 (m, 2H), 2.06-1.97 (m, 1H), 1.22 (d, J = 5.2 Hz, 6H),0.98-0.90 (m, 2H), 0.61- 0.54 (m, 2H) 56 I-56 AR N 812.5 11.11 (s, 1H),10.36 (s, 1H), 9.05 (s, 1H), 8.62-8.51 (m, 4H), 8.27 (d, J = 8.8 Hz,1H), 8.15 (s, 1H), 7.59-7.52 (m, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.12 (d,J = 8.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H),5.05 (dd, J = 5.2, 12.4 Hz, 1H), 4.56-4.39 (dd, J = 8.8, 49.6 Hz, 1H),3.64-3.51 (m, 14H), 2.93-2.81 (m, 1H), 2.64-2.52 (m, 3H), 2.06-1.97 (m,1H), 1.18 (s, 6H), 0.93 (d, J = 4.8 Hz, 2H), 0.58 (s, 2H) 57 I-57 AK L871.4 11.1 (s, 1H), 9.06 (d, J = 2.0 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H),8.86 (t, J = 5.6 Hz, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 7.72(s, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.03 (d, J= 7.2 Hz, 1H), 6.59(t, J = 5.6 Hz, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H),4.89- 4.69 (m, 1H), 3.72-3.66 (m, 1H), 3.59- 3.47 (m, 22H), 2.89-2.85(m, 1H), 2.65- 2.59 (m, 2H), 2.58-2.48 (m, 2H), 2.07- 1.98 (m, 1H),0.89-0.83 (m, 2H), 0.60- 0.56 (m, 2H) 58 I-58 AI BZ 776.4 11.1 (s, 1H),9.77 (s, 1H), 8.66-8.56 (m, 2H), 8.50 (s, 1H), 8.43 (s, 1H), 8.18 (d, J= 11.2 Hz, 1H), 7.92 (s, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 8.8Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.61 (t, J = 5.6 Hz, 1H), 5.10-5.01(m, 1H), 4.83- 4.63 (m, 1H), 3.66-3.62 (m, 1H), 3.56- 3.49 (m, 14H),2.87 (d, J = 14.8 Hz, 1H), 2.71-2.61 (m, 2H), 2.58-2.56 (m, 2H),2.06-1.97 (m, 1H), 0.86-0.85 (m, 2H), 0.53-0.47 (m, 2H) 59 I-59 AR L811.4 11.11 (s, 1H), 9.09-9.06 (m, 1H), 9.03 (d, J = 1.6 Hz, 1H),8.87-8.82 (m, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.61 (s, 1H), 7.71 (s,1H), 7.56 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.02 (d, J =6.8 Hz, 1H), 6.63-6.58 (m, 1H), 5.05 (dd, J = 5.6, 12.4 Hz, 1H),4.60-4.41 (m, 1H), 3.79-3.70 (m, 1H), 3.66-3.62 (m, 2H), 3.60-3.51 (m,10H), 2.91-2.82 (m, 1H), 2.63-2.55 (m, 2H), 2.55-2.53 (m, 2H), 2.07-1.98(m, 1H), 1.20 (s, 6H), 0.89-0.82 (m, 2H), 0.60-0.53 (m, 2H) 60 I-60 AP L899.7 11.10 (br s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.0 Hz,1H), 8.86 (t, J = 5.6 Hz, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 8.62 (s, 1H),7.72 (s, 1H), 7.60- 7.54 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J =7.2 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.06 (dd, J = 5.6, 12.8 Hz, 1H),4.60-4.43 (m, 1H), 3.79-3.64 (m, 1H), 3.63-3.59 (m, 2H), 3.56-3.43 (m,19H), 2.95-2.83 (m, 1H), 2.63-2.54 (m, 3H), 2.07-1.98 (m, 1H), 1.21 (s,6H), 0.89-0.83 (m, 2H), 0.60-0.55 (m, 2H) 61 I-61 AV N 740.3 11.11 (s,1H), 10.38 (s, 1H), 9.06 (s, 1H), 8.60-8.56 (m, 3H), 8.54 (s, 1H), 8.28(d, J = 9.2 Hz, 1H), 8.21 (s, 1H), 7.61-7.55 (m, 2H), 7.50 (d, J = 9.2Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.63 (t, J= 6.0 Hz, 1H), 5.06 (dd, J = 5.2, 13.2 Hz, 1H), 4.86- 4.66 (m, 1H),3.74-3.69 (m, 1H), 3.67- 3.60 (m, 8H), 3.51-3.49 (m, 2H), 2.92- 2.82 (m,1H), 2.65-2.54 (m, 2H), 2.58- 2.53 (m, 2H), 2.07-1.95 (m, 1H), 0.98-0.91 (m, 2H), 0.62-0.55 (m, 2H) 62 I-62 AM N 798.4 11.10 (s, 1H), 10.36(s, 1H), 9.05 (s, 1H), 8.59-8.50 (m, 4H), 8.27 (d, J = 8.8 Hz, 1H), 8.18(s, 1H), 7.59-7.54 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 8.8Hz, 1H), 7.02 (d, J = 6.6 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.05 (dd, J= 5.6, 12.6 Hz, 1H), 4.65-4.47 (m, 1H), 3.67-3.65 (m, 1H), 3.64-3.54 (m,14H), 2.93-2.86 (m, 1H), 2.65-2.54 (m, 2H), 2.56-2.54 (m, 1H), 2.06-1.97(m, 1H), 1.14 (t, J = 5.6 Hz, 3H), 0.97- 0.91 (m, 2H), 0.60-0.58 (m, 2H)63 I-63 AM L 797.4 11.10 (s, 1H), 9.07 (d, J = 1.6 Hz, 1H), 9.02 (d, J =2.0 Hz, 1H), 8.86-8.78 (m, 1H), 8.66 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H),8.57 (d, J = 6.4 Hz, 1H), 7.71 (d, J = 2.8 Hz, 1H), 7.56 (t, J = 7.6 Hz,1H), 7.12 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.59 (t, J =5.6 Hz, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 4.70-4.48 (m, 1H),3.73-3.66 (m, 1H), 3.63 (t, J = 5.2 Hz, 4H), 3.59-3.50 (m, 8H), 3.48-3.45 (m, 2H), 2.94-2.82 (m, 1H), 2.62- 2.55 (m, 2H), 2.55-2.53 (m, 1H),2.07- 1.98 (m, 1H), 1.15-1.12 (m, 3H), 0.90- 0.82 (m, 2H), 0.59-0.53 (m,2H) 64 I-64 AP N 900.6 (CD₃CN) δ 10.01 (br s, 1H), 9.04 (s, 1H), 8.58(d, J = 5.6 Hz, 1H), 8.51 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 8.19 (d,J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.52 (t, J =8.0 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.03 (s, 1H), 7.01(d, J = 2.4 Hz, 1H), 6.46 (t, J = 5.6 Hz, 1H), 4.98 (dd, J = 5.6, 12.8Hz, 1H), 4.56-4.39 (m, 1H), 3.90-3.74 (m, 1H), 3.66 (t, J = 5.2 Hz, 2H),3.63-3.47 (m, 17H), 3.43 (q, J = 5.2 Hz, 2H), 2.84-2.61 (m, 4H), 2.17-2.10 (m, 1H), 1.26 (s, 6H), 1.02-0.95 (m, 2H), 0.68-0.61 (m, 2H) 65 I-65AR BY 817.3 11.08 (s, 1H), 9.36 (s, 1H), 9.14 (s, 1H), 8.64 (s, 1H),8.43 (t, J = 5.6 Hz, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.95 (d, J = 8.8Hz, 1H), 7.63-7.52 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 6.8Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 6.40 (s, 1H), 5.04 (dd, J = 5.2, 12.4Hz, 1H), 4.55-4.36 (m, 1H), 3.64-3.44 (m, 14H), 2.93-2.82 (m, 1H),2.63-2.54 (m, 2H), 2.45-2.39 (m, 1H), 2.06-1.97 (m, 1H), 1.17 (s, 6H),0.80-0.74 (m, 2H), 0.51-0.46 (m, 2H) 66 I-66 AS L 885.5 11.10 (s, 1H),9.06 (d, J = 1.6 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.87-8.80 (m, 1H),8.66 (s, 1H), 8.63 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 1.6Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.03 (d, J= 7.2 Hz, 1H), 6.59 (t, J = 5.2 Hz, 1H), 5.05 (dd, J = 5.6, 12.8 Hz,1H), 4.73-4.49 (m, 1H), 3.74-3.64 (m, 2H), 3.61 (t, J = 5.2 Hz, 2H),3.58-3.47 (m, 17H), 3.45 (d, J = 5.4 Hz, 2H), 2.97-2.81 (m, 1H), 2.63-2.56 (m, 2H), 2.55-2.53 (m, 1H), 2.06- 1.96 (m, 1H), 1.19-1.13 (m, 3H),0.90- 0.83 (m, 2H), 0.57-0.55 (m, 2H) 67 I-67 AR BZ 804.4 11.10 (s, 1H),8.61-8.55 (m, 2H), 8.52 (s, 1H), 8.16 (dd, J = 1.6, 11.2 Hz, 1H), 7.91(s, 1H), 7.57-7.53 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 6.8Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H),4.56-4.37 (m, 1H), 3.67-3.49 (m, 14H), 2.94-2.82 (m, 1H), 2.63-2.52 (m,2H), 2.46-2.42 (m, 1H), 2.07-1.96 (m, 1H), 1.17 (s, 6H), 0.88-0.80 (m,2H), 0.53-0.46 (m, 2H) 68 I-68 AP BY 905.4 11.10 (s, 1H), 9.37 (s, 1H),9.15 (s, 1H), 8.66 (d, J = 2.0 Hz, 1H), 8.45 (t, J = 5.6 Hz, 1H), 8.40(s, 1H), 8.35 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.65-7.52 (m, 2H), 7.13(d, J = 8.8 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H),6.41 (s, 1H), 5.06 (dd, J = 5.2, 12.9 Hz, 1H), 4.63-4.34 (m, 1H), 3.68(d, J = 14.4 Hz, 1H), 3.63-3.59 (m, 2H), 3.57- 3.44 (m, 19H), 2.95-2.80(m, 1H), 2.64- 2.53 (m, 2H), 2.44-2.43 (m, 1H), 2.07-1.98 (m, 1H), 1.19(s, 6H), 0.83- 0.70 (m, 2H), 0.56-0.41 (m, 2H) 69 I-69 AP BZ 892.4 11.11(s, 1H), 9.73 (s, 1H), 8.66-8.51 (m, 3H), 8.44 (s, 1H), 8.17 (dd, J =1.6, 11.0 Hz, 1H), 7.92 (s, 1H), 7.58 (dd, J = 7.2, 8.4 Hz, 1H), 7.13(d, J = 8.4 Hz, 1H), 7.04 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H),5.08-5.03 (m, 1H), 4.62- 4.40 (m, 1H), 3.69-3.53 (m, 7H), 3.51- 3.33 (m,15H), 3.00-2.83 (m, 1H), 2.63-2.54 (m, 2H), 2.47 (s, 1H), 2.07- 1.95 (m,1H), 1.19 (s, 6H), 0.93-0.77 (m, 2H), 0.58-0.42 (m, 2H) 70 I-70 BT N798.3 11.10 (s, 1H), 10.37 (s, 1H), 9.06 (s, 1H), 8.61-8.53 (m, 4H),8.30-8.25 (m, 2H), 7.61-7.53 (m, 2H), 7.51 (d, J = 8.8 Hz, 1H), 7.13 (d,J = 8.4 Hz, 1H), 7.03 (d, J = 6.4 Hz, 1H), 6.61 (t, J = 5.6 Hz, 1H),5.05 (dd, J = 5.6, 13.2 Hz, 1H), 4.85-4.66 (m, 1H), 3.60-3.45 (m, 15H),2.93-2.87 (m, 1H), 2.63-2.56 (m, 2H), 2.56-2.53 (m, 1H), 2.06-1.98 (m,1H), 1.05 (d, J = 6.4 Hz, 3H), 0.98- 0.91 (m, 2H), 0.62-0.54 (m, 2H) 71I-71 BB L 841.4 11.10 (s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 9.03 (d, J =2.0 Hz, 1H), 8.86-8.79 (m, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.60- 8.55(m, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.12 (d, J= 8.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.06(dd, J = 5.6, 12.8 Hz, 1H), 4.69-4.48 (m, 1H), 3.71- 3.63 (m, 2H),3.62-3.60 (m, 2H), 3.60- 3.50 (m, 13H), 3.48-3.44 (m, 2H), 2.94-2.83 (m,1H), 2.62-2.55 (m, 2H), 2.55-2.53 (m, 1H), 2.07-1.97 (m, 1H), 1.19-1.13(m, 3H), 0.89-0.83 (m, 2H), 0.60-0.53 (m, 2H) 72 I-72 BA L 827.4 11.09(m, 1H), 9.07 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.85 (t, J= 5.6 Hz, 1H), 8.67 (s, 1H), 8.64 (s, 1H), 8.56 (s, 1H), 7.72 (s, 1H),7.57 (dd, J = 7.2, 8.4 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.03 (d, J =7.2 Hz, 1H), 6.60 (t, J = 5.6 Hz, 1H), 5.06 (dd, J = 5.6, 13.2 Hz, 1H),4.88-4.70 (m, 1H), 3.75-3.44 (m, 20H), 2.94-2.83 (m, 1H), 2.63-2.53 (m,3H), 2.07-1.99 (m, 1H), 0.90-0.83 (m, 2H), 0.60-0.54 (m, 2H) 73 I-73 BCL 855.3 11.07 (s, 1H), 9.06 (d, J = 1.6 Hz, 1H), 9.02 (d, J = 2.0 Hz,1H), 8.84 (t, J = 5.2 Hz, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H),7.71 (s, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.01(d, J = 6.8 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 5.2, 12.8Hz, 1H), 4.60- 4.40 (m, 1H), 3.79-3.57 (m, 4H), 3.55- 3.43 (m, 14H),2.94-2.81 (m, 1H), 2.62- 2.52 (m, 3H), 2.06-1.97 (m, 1H), 1.20 (s, 6H),0.89-0.81 (m, 2H), 0.60-0.52 (m, 2H) 74 I-74 AW N 724.1 11.10 (s, 1H),10.37 (s, 1H), 9.06 (s, 1H), 8.65-8.54 (m, 4H), 8.28 (d, J = 8.8 Hz,1H), 8.22 (s, 1H), 7.65-7.55 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.18 (d,J = 8.8 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.62 (t, J = 5.2 Hz, 1H),5.07 (dd, J = 5.2, 12.8 Hz, 1H), 4.65-4.37 (m, 1H), 3.84-3.60 (m, 3H),3.49-3.32 (m, 3H), 2.96-2.80 (m, 1H), 2.72-2.55 (m, 3H), 2.09-1.92 (m,1H), 1.23 (s, 6H), 1.01-0.89 (m, 2H), 0.60-0.57 (m, 2H) 75 I-75 AW L723.1 11.10 (s, 1H), 9.06 (dd, J = 2.0, 15.6 Hz, 2H), 8.92-8.84 (m, 1H),8.71-8.58 (m, 3H), 7.72 (s, 1H), 7.66-7.55 (m, 1H), 7.18 (d, J = 8.8 Hz,1H), 7.05 (d, J = 6.8 Hz, 1H), 6.62 (t, J = 5.6 Hz, 1H), 5.07 (dd, J =5.6, 12.8 Hz, 1H), 4.65-4.44 (m, 1H), 3.83-3.63 (m, 3H), 3.53-3.40 (m,3H), 2.93-2.80 (m, 1H), 2.58 (m, 3H), 2.09-1.96 (m, 1H), 1.25 (d, J =2.8 Hz, 6H), 0.89-0.84 (m, 2H), 0.59- 0.55 (m, 2H) 76 I-76 AV L 739.411.10 (s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.84(s, 1H), 8.67 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 7.71 (s, 1H),7.59-7.54 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H),6.65-6.60 (m, 1H), 5.05 (m, 1H), 4.87-4.71 (m, 1H), 3.75-3.60 (m, 9H),3.55 (m, 1H), 3.49 (m, 2H), 2.94-2.80 (m, 1H), 2.59 (s, 3H), 2.03 (m,1H), 0.89-0.84 (m, 2H), 0.57 (m, 2H) 77 I-77 AY N 710.3 11.10 (s, 1H),10.36 (s, 1H), 9.06 (s, 1H), 8.61-8.56 (m, 3H), 8.54 (d, J = 5.6 Hz,1H), 8.27 (d, J = 9.2 Hz, 1H), 8.22 (s, 1H), 7.63-7.55 (m, 2H), 7.51 (d,J = 8.8 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H),6.63 (s, 1H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H), 4.68-4.49 (m, 1H),3.69-3.64 (m, 7H), 2.91-2.83 (m, 1H), 2.63-2.58 (m, 2H), 2.54-2.53 (m,1H), 2.06-1.92 (m, 1H), 1.19 (d, J = 5.2 Hz, 3H), 0.98-0.92 (m, 2H),0.58 (s, 2H)  78^(c) I-78 tert-butyl N- CE 837.3 (CD₃CN) δ 9.08 (br s,1H), 8.43 (s, 1H), [2-[2-[2-[2-(2- 8.17 (br s, 1H), 7.89 (d, J = 5.6 Hz,1H), aminoethoxy)- 7.74 (s, 1H), 7.54-7.48 (m, 1H), 7.34 ethoxy]- (d, J= 5.6 Hz, 1H), 7.09 (br s, 1H), 7.03- ethoxy]ethoxy]- 6.97 (m, 2H), 6.45(t, J = 5.6 Hz, 1H), ethyl]carbamate 4.98-4.81 (m, 2H), 4.68-4.64 (m,1H), (CAS# 4.36 (dd, J = 6.4, 11.2 Hz, 1H), 4.19- 01187-40-0) 4.13 (m,1H), 4.06 (s, 3H), 3.66-3.52 (m, 18H), 3.42 (q, J = 5.6 Hz, 2H), 2.79-2.59 (m, 4H), 2.13-2.08 (m, 1H), 1.80- 1.62 (m, 2H), 1.10 (t, J = 7.2Hz, 3H) 79 I-79 AU L 767.4 11.09 (s, 1H), 9.07 (s, 1H), 9.03 (s, 1H),8.85-8.79 (m, 1H), 8.67 (s, 1H), 8.62 (s, 1H), 8.60 (s, 1H), 7.71 (s,1H), 7.56 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.02 (d, J =7.2 Hz, 1H), 6.65- 6.60 (m, 1H), 5.07-5.01 (m, 1H), 4.57- 4.55 (m, 1H),3.76-3.69 (m, 1H), 3.68- 3.63 (m, 2H), 3.57-3.48 (m, 6H), 2.89- 2.81 (m,1H), 2.63-2.55 (m, 4H), 2.05- 1.96 (m, 1H), 1.20 (s, 6H), 0.88-0.83 (m,2H), 0.60-0.53 (m, 2H) 80 I-80 AU N 768.4 11.10 (s, 1H), 10.36 (s, 1H),9.06 (s, 1H), 8.59-8.51 (m, 4H), 8.28 (d, J = 8.8 Hz, 1H), 8.22 (s, 1H),7.60-7.54 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H),7.02 (d, J = 7.2 Hz, 1H), 6.63 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 5.6,12.8 Hz, 1H), 4.57-4.38 (m, 1H), 3.75-3.70 (m, 1H), 3.68-3.56 (m, 8H),2.90-2.82 (m, 1H), 2.64-2.58 (m, 2H), 2.57-2.55 (m, 1H), 2.54-2.53 (m,1H), 2.05-1.96 (m, 1H), 1.19 (s, 6H), 0.97-0.92 (m, 2H), 0.61-0.55 (m,2H) 81 I-81 AX N 696.3 11.1 (s, 1H), 10.4 (s, 1H), 9.06 (s, 1H),8.60-8.56 (m, 3H), 8.54 (s, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.21 (s, 1H),7.63- 7.56 (m, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H),7.05 (d, J = 6.8 Hz, 1H), 6.69-6.61 (m, 1H), 5.08- 5.03 (m, 1H),4.89-4.68 (m, 1H), 3.77- 3.56 (m, 8H), 2.92-2.86 (m, 1H), 2.64- 2.59 (m,2H), 2.57-2.55 (m, 1H), 2.05- 1.96 (m, 1H), 0.97-0.92 (m, 2H), 0.61-0.57 (m, 2H) 82 I-82 Aχ L 695.3 11.1 (s, 1H), 9.09 (d, J = 2.0 Hz, 1H),9.05 (d, J = 2.0 Hz, 1H), 8.90 (t, J = 5.2 Hz, 1H), 8.70 (s, 1H), 8.65(s, 1H), 8.63 (s, 1H), 7.80 (s, 1H), 7.60 (dd, J = 7.2, 8.4 Hz, 1H),7.18 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.0 Hz, 1H), 6.69-6.61 (m, 1H),5.06 (dd, J = 5.5, 12.9 Hz, 1H), 4.91-4.72 (m, 1H), 3.75-3.65 (m, 4H),3.54-3.51 (m, 4H), 2.93-2.82 (m, 1H), 2.71-2.56 (m, 3H), 2.07-1.99 (m,1H), 0.90-0.84 (m, 2H), 0.62-0.57 (m, 2H) 83 I-83 AY L 709.3 11.09 (s,1H), 9.07 (d, J = 1.6 Hz, 1H), 9.04 (d, J = 1.6 Hz, 1H), 8.86 (s, 1H),8.67 (s, 1H), 8.64 (s, 1H), 8.56 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.60(t, J = 8.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 6.8 Hz, 1H),6.64 (s, 1H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H), 4.75- 4.51 (m, 1H),3.83-3.43 (m, 7H), 2.94- 2.81 (m, 1H), 2.62-2.56 (m, 2H), 2.55- 2.54 (m,1H), 2.02 (d, J = 9.6 Hz, 1H), 1.24-1.17 (m, 3H), 0.89-0.84 (m, 2H),0.60-0.55 (m, 2H) 84 I-84 AZ N 754.4 11.11 (s, 1H), 10.37 (s, 1H), 9.06(s, 1H), 8.63-8.40 (m, 3H), 8.33-8.18 (m, 2H), 7.60-7.48 (m, 3H), 7.15(d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.63 (t, J = 5.6 Hz, 1H),5.05 (dd, J = 5.6, 12.8 Hz, 1H), 4.66-4.45 (m, 2H), 3.74-3.41 (m, 11H),2.93-2.82 (m, 1H), 2.69-2.58 (m, 3H), , 2.06-1.97 (m, 1H), 1.23-1.12 (m,3H), 1.01-0.89 (m, 2H), 0.58 (m, 2H) 85 I-85 AZ L 753.4 11.09 (s, 1H),9.07 (d, J = 2.0 Hz, 2H), 9.03 (s, 1H), 8.86-8.76 (m, 1H), 8.70- 8.61(m, 2H), 8.60-8.52 (m, 1H), 7.74- 7.67 (m, 1H), 7.56 (m, 1H), 7.14 (d, J= 8.8 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.62 (t, J = 5.6 Hz, 1H), 5.05(dd, J = 5.2, 12.8 Hz, 1H), 4.72-4.48 (m, 1H), 3.76-3.45 (m, 11H),2.97-2.80 (m, 1H), 2.64-2.54 (m, 3H), 2.09-1.96 (m, 1H), 1.24-1.12 (m,3H), 0.90-0.82 (m, 2H), 0.57 (m, 2H) 86 I-86 AT L 795.1 11.1 (s, 1H),9.07 (d, J = 2.0 Hz, 1H), 9.02 (d, J = 2.0 Hz, 1H), 8.85 (t, J = 5.6 Hz,1H), 8.66 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 7.71 (s, 1H), 7.57 (t, J= 8.0 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H),6.71-6.61 (m, 1H), 5.07- 5.00 (m, 1H), 4.57-4.41 (m, 1H), 3.80- 3.46 (m,10H), 2.95-2.80 (m, 1H), 2.63-2.55 (m, 3H), 2.06-1.97 (m, 1H), 1.87-1.78(m, 2H), 1.77-1.68 (m, 2H), 1.18 (s, 6H), 0.89-0.83 (m, 2H), 0.61- 0.53(m, 2H) 87 I-87 tert-butyl N- CE 749.1 11.10 (s, 1H), 8.88 (s, 1H), 8.43(t, J = [2-[2-(2- 5.6 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J = aminoethoxy)-5.6 Hz, 1H), 7.72 (s, 1H), 7.58-7.51 ethoxy]ethyl]- (m, 1H), 7.42 (d, J= 5.6 Hz, 1H), 7.10 carbamate (d, J = 8.4 Hz, 1H), 6.99 (d, J = 7.2 Hz,(CAS# 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 153086-78-3) 5.6,12.8 Hz, 1H), 4.99-4.82 (m, 1H), 4.54 (dd, J = 3.6, 11.2 Hz, 1H), 4.25(dd, J = 6.4, 11.2 Hz, 1H), 4.13- 4.04 (m, 1H), 3.96 (s, 3H), 3.68-3.56(m, 8H), 3.50-3.43 (m, 4H), 2.94-2.81 (m, 1H), 2.62-2.53 (m, 3H),2.07-1.97 (m, 1H), 1.65-1.56 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H) 88 I-88BE L 797.3 11.05 (s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 9.03 (d, J = 2.0 Hz,1H), 8.87 (t, J = 5.6 Hz, 1H), 8.66 (d, J = 6.0 Hz, 2H), 8.58 (s, 1H),7.72 (s, 1H), 7.60-7.51 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.02 (d, J =6.8 Hz, 1H), 6.59 (t, J = 6.0 Hz, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H),4.88- 4.67 (m, 1H), 3.65-3.60 (m, 2H), 3.58- 3.46 (m, 14H), 2.94-2.83(m, 1H), 2.63- 2.54 (m, 3H), 2.08-1.98 (m, 1H), 1.96- 1.75 (m, 2H),0.90-0.80 (m, 2H), 0.61- 0.51 (m, 2H) Variations of temperature and timefor Method 7 were as follows: Step 1 was run a from 0.5-3 hrs; Step 2was run from 15-60 minutes; Step 3 was run at 110-115° C. for 14-136hrs, with most complete within 40-60 h. ^(a)mass is (M + Na)⁺. ^(b)Step1 was run at rt for 12 h. ^(c)Step 3 was run at 90° C. for 12 h. ^(d)Theproduct of Step 1 was purified by silica gel chromatography (DCM:MeOH =25:1) instead of prep-HPLC.

Further Examples Using Synthetic Methods Similar to Method 7 Example 89:1-[[(2S,3S,4S)-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide,I-89

Step 1—Tert-Butyl(14-((2S,3S,4S)-2-(((6-cyano-7-methoxyisoquinolin-1-yl)oxy)methyl)-3-ethyl-4-fluoro-5-oxopyrrolidin-1-yl)-3,6,9,12-tetraoxatetradecyl)carbamate

To a solution of1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carbonitrile(50 mg, 145.6 umol, Intermediate CD) in DMF (3 mL) was added NaH (11.7mg, 291 umol, 60% dispersion in mineral oil) at 0° C. The reactionmixture was stirred at 0° C. for 1 hr. Then,2-[2-[2-[2-[2-(tert-butoxycarbonyl-amino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (90.8 mg, 218 umol, synthesized via Steps 1-2 ofIntermediate AK) was added. The resulting reaction mixture was allowedto warm to rt and stirred for 12 h. On completion, the reaction mixturewas quenched with water (2 mL) and extracted with ethyl acetate (3×200mL). The combined organic layers were washed with saturated brinesolution (50 mL), dried over with anhydrous sodium sulfate, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by prep-HPLC (column: Gemini 150*25 5u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B %: 15%-75%) to give the titlecompound (25 mg, 25% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃)δ 8.03 (s, 1H), 7.93 (d, J=5.6 Hz, 1H), 7.75 (s, 1H), 7.20 (d, J=5.6 Hz,1H), 5.10-4.92 (m, 2H), 4.85 (dd, J=3.2, 12.4 Hz, 1H), 4.45 (dd, J=2.4,12.4 Hz, 1H), 4.32-4.25 (m, 1H), 4.03 (s, 3H), 3.68-3.50 (m, 18H),3.32-3.31 (m, 2H), 2.65-2.42 (m, 1H), 1.88-1.76 (m, 1H), 1.69-1.63 (m,1H), 1.44 (s, 9H), 1.11 (t, J=7.2 Hz, 3H). LC-MS (ESI⁺) m/z 663.2(M+H)⁺.

Step 2—Tert-Butyl(14-((2S,3S,4S)-2-(((6-carbamoyl-7-methoxyisoquinolin-1-yl)oxy)methyl)-3-ethyl-4-fluoro-5-oxopyrrolidin-1-yl)-3,6,9,12-tetraoxatetradecyl)carbamate

To a solution of tert-butylN-[2-[2-[2-[2-[2-[(2S,3S,4S)-2-[(6-cyano-7-methoxy-1-isoquinolyl)oxymethyl]-3-ethyl-4-fluoro-5-oxo-pyrrolidin-1yl]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(20 mg, 30.2 umol) in DMSO (1 mL) was added K₂CO₃ (4.17 mg, 30.2 umol)at rt. Then, H₂O₂ (6.84 mg, 60.4 umol, 30% solution) was added slowly.The reaction mixture was stirred at rt for 3 h. On completion, thereaction mixture was diluted with water (3 mL) and extracted with ethylacetate (3×20 mL). The combined organic layers were washed with brine(10 mL), dried over anhydrous sodium sulfate, filtered and concentratedin vacuo to give the title compound (18 mg, 88% yield) as a colorlessoil. LC-MS (ESI⁺) m/z 703.2 (M+H)⁺.

Step3—1-(((2S,3S,4S)-1-(14-amino-3,6,9,12-tetraoxatetradecyl)-3-ethyl-4-fluoro-5-oxopyrrolidin-2-yl)methoxy)-7-methoxyisoquinoline-6-carboxamide

To a solution of tert-butylN-[2-[2-[2-[2-[2-[(2S,3S,4S)-2-[(6-carbamoyl-7-methoxy-1-isoquinolyl)oxymethyl]-3-ethyl-4-fluoro-5-oxo-pyrrolidin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]-ethyl]carbamate(18.0 mg, 26.44 umol) in DCM (2 mL) was added HCl in dioxane (4 M, 1mL). The reaction mixture was stirred at rt for 30 min. On completion,the reaction mixture was concentrated in vacuo to give the titlecompound (16.3 mg, 99% yield, hydrochloride salt). LC-MS (ESI⁺) m/z603.2 (M+H)⁺.

Step4—1-[[(2S,3S,4S)-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide

To a solution of1-[[(2S,3S,4S)-1-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethyl]-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide(16.3 mg, 26.5 umol, HCl salt) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (9.50 mg, 34.4umol, Intermediate R) in dioxane (5 mL) was added DIPEA (34.2 mg, 46 uL,264 umol). The reaction mixture was stirred at 120° C. for 76 hrs. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 35%-65%) to give the titlecompound I-89 (10.0 mg, 42% yield,) as a yellow solid. ¹H NMR (400 MHz,CD₃CN) δ 9.09 (s, 1H), 8.45 (s, 1H), 7.91 (d, J=6.0 Hz, 1H), 7.73 (s,1H), 7.64 (s, 1H), 7.57-7.50 (m, 1H), 7.36 (d, J=6.0 Hz, 1H), 7.04 (s,1H), 7.02 (d, J=1.6 Hz, 1H), 6.48 (t, J=5.2 Hz, 1H), 6.39 (s, 1H),5.08-4.95 (m, 1H), 4.92 (dd, J=6.0, 8.4 Hz, 1H), 4.81 (dd, J=3.6, 12.4Hz, 1H), 4.46 (dd, J=3.2, 12.4 Hz, 1H), 4.30-3.80 (m, 1H), 4.02 (s, 3H),3.82-3.80 (m, 1H), 3.71-3.42 (m, 18H), 3.41-3.33 (m, 1H), 2.84-2.48 (m,4H), 2.14-2.09 (m, 1H), 1.81-1.63 (m, 2H), 1.08 (t, J=7.2 Hz, 3H). LC-MS(ESI⁺) m/z 837.1 (M+H)⁺.

Example 90:(2S)-3-[(8R)-1-[4-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]piperazin-1-yl]cyclohexoxy]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]-2-hydroxy-propanamide,I-90

To a solution of(2S)-2-hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide(80.0 mg, 160 umol, HCl salt, Intermediate DR) in DMF (2 mL) was addedK₂CO₃ (89.0 mg, 643 umol) and2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy] ethyl methanesulfonate(79.0 mg, 241 umol, synthesized via Step 1 of Intermediate A1), and themixture was stirred at 60° C. for 20 h. On completion, the reactionmixture was concentrated in vacuo to give a residue. The residue waspurified by reverse phase chromatography (0.1% NH3H₂O) to givetert-butylN-[2-[2-[2-[4-[4-[[(8R)-8-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamateI-90 (60.0 mg, 53% yield) as a light yellow solid (LC-MS (ESI⁺) m/z677.5 (M+H)⁺). Steps 2 & 3 followed Method 7, where Step 2 was run at rtfor 1 h and Step 3 used fluoride Intermediate R for the coupling at 115°C. for 20 h. Characterization of the final product: ¹H NMR (400 MHz,DMSO-d₆) δ 11.13 (s, 1H), 8.52 (m, 1H), 7.59 (dd, J=7.6, 8.4 Hz, 1H),7.23-7.09 (m, 3H), 7.05 (d, J 7.2 Hz, 1H), 6.60 (t, J 5.6 Hz, 1H),5.17-5.09 (m, 1H), 5.05 (dd, J 5.2, 12.8 Hz, 1H), 3.91 (t, J=6.8 Hz,1H), 3.64-3.61 (m, 3H), 3.59-3.53 (m, 7H), 3.18-3.14 (s, 2H), 3.11-2.80(m, 4H), 2.64-2.54 (m, 3H), 2.43-2.25 (m, 10H), 2.20-1.97 (m, 4H),1.84-1.81 (m, 2H), 1.70-1.43 (m, 4H), 1.41-1.27 (m, 2H). LC-MS (ESI⁺)m/z 833.4 (M+H)⁺.

Example 91:(2R)-3-[(8R)-1-[4-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]piperazin-1-yl]cyclohexoxy]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]-2-hydroxy-propanamide,I-91

To a mixture of(2R)-2-hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide (60.0 mg, 124 umol,Intermediate EM) in DMF (2 mL) was added K₂CO₃ (68.8 mg, 497 umol) and2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate(81.5 mg, 248 umol, synthesized via Step 1 of Intermediate A1). Then thereaction mixture was stirred at 60° C. for 12 hours. On completion, thereaction mixture was concentrated in vacuo. The crude product waspurified by revered phase (FA) to give tert-butylN-[2-[2-[2-[4-[4-[[(8R)-8-[(2R)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethyl]carbamateI-91 (75.0 mg, 63% yield) as yellowish oil. LC-MS (ESI⁺) m/z 677.2(M+H)⁺. Steps 2 & 3 followed Method 7, where Step 2 was run at rt for 30min and Step 3 used fluoride Intermediate R for the coupling at 115° C.for 12 h. Characterization of the final product: ¹H NMR (400 MHz,DMSO-d₆) δ 11.13 (s, 1H), 8.60-8.48 (m, 1H), 7.66-7.50 (m, 1H),7.21-7.14 (m, 2H), 7.12 (s, 1H), 7.06 (d, J=7.2 Hz, 1H), 6.61 (t, J=5.6Hz, 1H), 5.19-5.11 (m, 1H), 5.06 (dd, J=5.6, 13.2 Hz, 1H), 3.86-3.84 (m,1H), 3.72-3.57 (m, 10H), 2.98-2.85 (m, 2H), 2.66-2.55 (m, 2H), 2.48-2.40(m, 8H), 2.37-2.23 (m, 4H), 2.18-1.99 (m, 4H), 1.85 (d, J=11.6 Hz, 2H),1.74-1.46 (m, 4H), 1.44-1.26 (m, 2H); LC-MS (ESI⁺) m/z 833.1 (M+H)⁺.

Example 92:N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxymethyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]-4-carboxamide,I-92

To a solution of tert-butylN-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (88.0 mg, 354 umol, CAS#139115-92-7) in THF (10 mL) was added Na metal (20 mg, 886 umol). Afterstirring for minutes at rt,N-[1-[4-(bromomethyl)phenyl]-3-carbamoyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(200 mg, 354 umol, Intermediate CV) was added. The mixture was stirredat rt for 30 hours. On completion, the mixture was concentrated invacuo. The residue was purified by reverse phase chromatography to givetert-butylN-[2-[2-[2-[[4-[3-carbamoyl-4-[[2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-pyrazol-1-yl]phenyl]methoxy]ethoxy]ethoxy]ethyl]carbamate(30.0 mg, 12% yield) as white solid. LC-MS (ESI⁺) m/z 733.3 (M+H)⁺.

Steps 2 & 3 followed Method 7 as described above where the deprotectionwas run at rt for 2 h. Intermediate R was used as the fluorine couplingpartner in the last step, where the reaction was run at 115° C. for 72hours. The final product was purified by pre-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:40%-70%, 22 min) to give the title compound I-92 (5.03 mg, 14% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.10 (s, 1H), 11.01 (s, 1H),9.03 (s, 1H), 8.93 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.06 (s, 1H),7.99-7.88 (d, J 8.0 Hz, 2H), 7.81-7.66 (m, 2H), 7.57 (t, J=7.6 Hz, 1H),7.50-7.46 (m, 2H), 7.27 (s, 1H), 7.20-7.12 (m, 2H), 7.03 (d, J=7.2 Hz,1H), 6.61 (m, 1H), 5.05 (dd, J=5.2, 12.8 Hz, 1H), 4.54 (s, 2H),4.35-4.16 (m, 2H), 3.69-3.46 (m, 12H), 2.95-2.81 (m, 1H), 2.60-2.57 (m,2H), 2.06-1.97 (m, 1H); LC-MS (ESI⁺) m/z 889.8 (M+H)⁺.

Example 93:4-(Cyclopropylamino)-N-[3-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]-1-methyl-ethoxy]ethoxy]ethoxy]-2-fluoro-propyl]-6-(1,6-naphthyridin-2-ylamino)pyridine-3-carboxamide,I-93

4-(cyclopropylamino)-N-[3-[2-[2-[2-(1,3-dioxoisoindolin-2-yl)-1-methyl-ethoxy]-ethoxy]ethoxy]-2-fluoro-propyl]-6-(1,6-naphthyridin-2-ylamino)pyridine-3-carboxamidewas synthesized via Step 1 of Method 7, coupling amine BU with acidIntermediate N. This compound was then deprotected in Step 2 usinghydrazine hydrate dissolved in EtOH and stirring at 80° C. for 14 hours.On completion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by reversed phase chromatography (0.1%NH₃ H₂O) to give the title compound I-93 (120 mg, 65% yield) as a brownsolid. (L C-MS (ESI)⁺ m/z 542.3. (M+H)⁺). Step 3 followed Method 7,where fluoride Intermediate R was utilized. Final productcharacterization: ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (br s, 1H), 10.37(s, 1H), 9.06 (s, 1H), 8.60-8.51 (m, 4H), 8.31-8.24 (m, 2H), 7.60-7.54(m, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.03 (d, J=7.2Hz, 1H), 6.60 (t, J=5.6 Hz, 1H), 5.06 (dd, J=5.6, 12.8 Hz, 1H),4.83-4.65 (m, 1H), 3.72-3.20 (m, 15H), 2.95-2.84 (m, 1H), 2.65-2.54 (m,3H), 2.08-1.99 (m, 1H), 1.15 (d, J=6.4 Hz, 3H), 0.98-0.91 (m, 2H),0.62-0.56 (m, 2H); LC-MS (ESI)⁺ m/z 798.3. (M+H)⁺.

Example 94:6-(5-Cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-(3-(2-((2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)amino)ethoxy)-2-fluoropropyl)nicotinamide,I-94

Tert-butyl(2-(3-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)-2-fluoropropoxy)ethyl)(2-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)ethyl)carbamatewas synthesized using Step 1 of Method 7 by coupling amine IntermediateBH with acid Intermediate L. For Step 2, the amine was deprotectedN₂H₄H₂O (54.8 mg, 1.07 mmol) in EtOH (4 mL). The mixture was stirred at80° C. for 2 hrs. On completion, the reaction mixture was filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by prep-TLC (SiO₂, DCM:MeOH=4/1) to give tert-butyl(2-(2-aminoethoxy)ethyl)(2-(3-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)-2-fluoropropoxy)ethyl)carbamate(45.0 mg, 92.2% yield) as colorless oil (LC-MS (ESI)⁺ m/z 626.2.(M+H)⁺). Step 3 coupled Intermediate R as the fluoride under theconditions described for Method 7. The final compound was deprotected bydissolving tert-butyl(2-(3-(6-(5-cyano-1H-pyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)nicotinamido)-2-fluoropropoxy)ethyl)(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethyl)carbamate(39 mg, 44.2 mg) in DCM (2 mL) and adding HCl in dioxane (4 M, 0.5 mL).The reaction mixture was stirred at 25° C. for 0.5 hr. On completion,the reaction mixture was diluted with MeCN (2 mL) and basified withNaHCO₃ solid until the pH=7. After filtration, the mixture was purifieddirectly by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um;mobile phase: [water (0.225% FA)-ACN]) to give the title compound I-94(2.06 mg, 3.7% yield, FA salt) as a yellow solid. ¹H NMR (400 MHz, DMSO)δ 11.1 (s, 1H), 9.05 (d, J=2.0 Hz, 1H), 9.01 (d, J=2.0 Hz, 1H), 8.83 (t,J=5.6 Hz, 1H), 8.65 (s, 1H), 8.61 (s, 1H), 8.53 (s, 1H), 8.34 (s, 1H),7.70 (s, 1H), 7.55 (s, J=7.2 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.01 (d,J=7.2 Hz, 1H), 6.61 (d, J=6.0 Hz, 1H), 5.09-5.00 (m, 1H), 4.88-4.70 (m,1H), 3.70-3.50 (m, 5H), 2.95-2.84 (m, 2H), 2.80-2.63 (m, 9H), 2.37-2.30(m, 4H), 2.05-1.98 (m, 1H), 0.85 (dd, J=6.8, 11.6 Hz, 2H), 0.55 (dd,J=6.8, 11.6 Hz, 2H); LC-MS (ESI)⁺ m/z 804.2. (M+Na)⁺.

Example 95 (Method 8):6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-[3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]ethoxy]ethoxy]-2-fluoro-propyl]pyridine-3-carboxamide,I-95

Step 1—Tert-ButylN-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoropropoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-(3-amino-2-fluoro-propoxy)ethoxy]ethyl]carbamate (100 mg, 356umol, Intermediate AV) and6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxylicacid (171 mg, 535 umol, Intermediate L) in DMF (3.00 mL) was added HATU(162 mg, 428 umol) and DIPEA (138 mg, 1.07 mmol, 186 uL). The mixturewas stirred at rt for 1 hour. On completion, the mixture was dilutedwith water (30 mL) and extracted with EA (3×30 mL). The organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The residue was purified by reverse phase (0.1% NH₃ H₂O) to give thetitle compound (80.0 mg, 38% yield) as a yellow oil. LC-MS (ESI⁺) m/z583.3 (M+H)⁺.

Step2—N-[3-[2-(2-aminoethoxy)ethoxy]-2-fluoro-propyl]-6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxamide

To a solution of tert-butylN-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-propoxy]ethoxy]ethyl]carbamate (80.0mg, 137 umol) in DCM (4.00 mL) was added HCl in dioxane (4 M, 2.00 mL)and the mixture was stirred at rt for 30 minutes. On completion, themixture was concentrated in vacuo to give the title compound (70.0 mg,98% yield) as white solid. LC-MS (ESI⁺) m/z 483.2 (M+H)⁺.

Step3—6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-[3-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]ethoxy]ethoxy]-2-fluoro-propyl]pyridine-3-carboxamide

To a solution ofN-[3-[2-(2-aminoethoxy)ethoxy]-2-fluoro-propyl]-6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxamide(50.0 mg, 96.3 umol, HCl) and2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetic acid(32.0 mg, 96.3 umol, Intermediate CA) in DMF (2.00 mL) was added HATU(43.9 mg, 115 umol) and DIPEA (62.2 mg, 481 umol, 83.9 uL). The mixturewas stirred at rt for 1 hour. On completion, the mixture was dilutedwith H₂O (30 mL) and extracted with EA (3×15 mL). The organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.The mixture was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 20%-50%, 10min) to give the title compound I-95 (35.36 mg, 43% yield, FA) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.1 (s, 1H), 9.06 (d, J=1.6Hz, 1H), 9.02 (d, J=1.6 Hz, 1H), 8.91-8.81 (m, 1H), 8.66 (s, 1H), 8.62(s, 1H), 8.54 (s, i1H), 8.07-7.98 (m, 1H), 7.82-7.76 (m, 1H), 7.71 (s,1H), 7.48 (d, J=7.2 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 5.13-5.09 (m, 1H),4.79 (s, 2H), 4.88-4.71 (m, 1H), 3.61-3.46 (m, 12H), 2.95-2.83 (m, 1H),2.63-2.54 (m, 3H), 2.09-2.02 (m, 1H), 0.89-0.83 (m, 2H), 0.60-0.53 (m,2H); LC-MS (ESI⁺) m/z 797.4 (M+H)⁺.

TABLE 6 Compounds synthesized via Method 8 with the coupling of variousamines and acids in Step 1, followed by coupling with acid IntermediateCA in Step 3. LCMS (ES+) Intermediate Intermediate m/z Ex-# I-# AmineAcid (M + H)⁺ HNMR (400 MHz, DMSO-d6) δ 96 I-96 AI N 842.4 12.08 (s,1H), 11.14 (s, 1H), 9.61 (s, 1H), 9.13 (s, 1H), 8.95 (s, 1H), 8.86 (d, J= 6.8 Hz, 1H), 8.70 (d, J = 8.8 Hz, 1H), 8.50 (s, 1H), 8.34 (d, J = 6.4Hz, 1H), 8.02 (t, J = 5.6 Hz, 1H), 7.83-7.79 (m, 1H), 7.55 (d, J = 8.8Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.14 (s,1H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 4.88-4.73 (m, 3H), 3.75-3.60 (m,6H), 3.53-3.44 (m, 6H), 3.34-3.30 (m, 2H), 2.97-2.84 (m, 2H), 2.71 (s,1H), 2.60-2.57 (m, 1H), 2.56-2.52 (m, 2H), 2.10-1.98 (m, 1H), 0.99-0.91(m, 2H), 0.73-0.69 97 I-97 AK N 930.5 11.14 (s, 1H), 10.38 (s, 1H), 9.05(s, 1H), 8.60-8.55 (m, 3H), 8.47 (s, 1H), 8.27 (d, J = 9.0 Hz, 1H), 8.19(s, 1H), 8.02 (t, J = 5.6 Hz, 1H), 7.80 (dd, J = 7.6, 8.4 Hz, 1H), 7.57(d, J = 5.6 Hz, 1H), 7.54-7.44 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 5.12(dd, J = 5.6, 12.8 Hz, 1H), 4.87-4.65 (m, 3H), 3.73-3.51 (m, 12H),3.50-3.40 (m, 10H), 3.37-3.21 (m, 2H), 2.99-2.84 (m, 1H), 2.65-2.56 (m,2H), 2.55 (d, J = 4.4 Hz, 1H), 2.10- 2.02 (m, 1H), 1.04-0.89 (m, 2H),0.69- 0.52 (m, 2H) 98 I-98 BA N 886.1 13.12 (s, 1H), 11.14 (s, 1H), 9.64(s, 1H), 9.32 (s, 1H), 8.93 (s, 1H), 8.86 (d, J = 6.4 Hz, 1H), 8.73 (d,J = 8.8 Hz, 1H), 8.63 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 8.12-8.03 (m,1H), 7.85-7.73 (m, 2H), 7.48 (d, J = 7.2 Hz, 1H), 7.43 (s, 1H), 7.39 (d,J = 8.2 Hz, 1H), 5.12 (dd, J = 5.2, 12.6 Hz, 1H), 4.90-4.73 (m, 3H),3.74-3.56 (m, 12H), 3.48-3.44 (m, 4H), 3.38-3.08 (m, 2H), 3.04-2.80 (m,2H), 2.68-2.62 (m, 2H), 2.55-2.52 (m, 2H), 2.07-1.99 (m, 1H), 0.98-0.90(m, 2H), 0.74-0.66 (m, 2H) 99 I-99 AV N 798.3 11.15 (s, 1H), 10.38 (s,1H), 9.06 (s, 1H), 8.61-8.55 (m, 3H), 8.53 (s, 1H), 8.28 (d, J = 9.2 Hz,1H), 8.22 (s, 1H), 8.04 (t, J = 5.6 Hz, 1H), 7.86-7.72 (m, 1H), 7.57 (d,J = 5.6 Hz, 1H), 7.52- 7.44 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 5.12 (dd,J = 5.2, 12.8 Hz, 1H), 4.83- 4.66 (m, 3H), 3.71-3.68 (m, 1H), 3.66- 3.56(m, 10H), 2.94-2.88 (m, 1H), 2.65-2.58 (m, 2H), 2.57- 2.53 (m, 2H),2.08-2.00 (m, 1H), 0.95 (d, J = 5.2 Hz, 2H), 0.63-0.55 (s, 2H) 100 I-100BV N 826.5 11.13 (s, 1H), 10.37 (s, 1H), 9.06 (s, 1H), 8.60-8.55 (m,3H), 8.46 (s, 1H), 8.28 (d, J = 9.2 Hz, 1H), 8.21 (s, 1H), 7.95 (t, J =5.6 Hz, 1H), 7.85-7.78 (m, 1H), 7.57 (d, J = 6.0 Hz, 1H), 7.53- 7.47 (m,2H), 7.39 (d, J = 8.4 Hz, 1H), 5.14-5.10 (m, 1H), 4.84-4.68 (m, 3H),3.67-3.57 (m, 2H), 3.55-3.41 (m, 8H), 3.25-3.18 (m, 2H), 2.88 (m, 1H),2.70- 2.61 (m, 2H), 2.37-2.30 (m, 1H), 2.09- 2.00 (m, 1H), 1.79-1.63 (m,4H), 0.98- 0.92 (m, 2H), 0.63-0.55 (m, 2H) 101 I-101 AU L 825.4 11.18(s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 9.04 (d, J = 2.0 Hz, 1H), 8.85-8.80(m, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.60- 8.59 (m, 1H), 8.01 (t, J =5.6 Hz, 1H), 7.80-7.75 (m, 1H), 7.71 (s, 1H), 7.46 (d, J = 7.2 Hz, 1H),7.39 (d, J = 8.8 Hz, 1H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 4.79 (s, 2H),4.59-4.42 (m, 1H), 3.80- 3.62 (m, 2H), 3.58-3.46 (m, 6H), 3.46- 3.43 (m,1H), 2.95-2.83 (m, 1H), 2.65- 2.60 (m, 1H), 2.60-2.56 (m, 2H), 2.55-2.54 (m, 1H), 2.07-2.02 (m, 1H), 1.21 (s, 6H), 0.89-0.83 (m, 2H),0.60-0.55 (m, 2H) 102 I-102 BG L 795.4 11.13 (s, 1H), 9.07 (d, J = 1.6Hz, 1H), 9.03 (d, J = 2.0 Hz, 1H), 8.88-8.82 (m, 1H), 8.67 (s, 1H), 8.63(s, 1H), 8.56 (s, 1H), 7.96 (s, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.72 (s,1H), 7.49 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 5.12 (dd, J =5.2, 12.8 Hz, 1H), 4.89-4.69 (m, 3H), 3.69-3.41 (m, 4H), 3.20-3.12 (m,2H), 2.96-2.84 (m, 1H), 2.68-2.66 (m, 1H), 2.64-2.56 (m, 3H), 2.34-2.30(m, 1H), 2.04-2.00 (m, 1H), 1.57-1.43 (m, 4H), 1.33-1.30 (m, 2H),0.87-0.80 (m, 2H), 0.58-0.56 (m, 2H) 103 I-103 tert-butyl N- CE 895.411.12 (br s, 1H), 8.88 (s, 1H), 8.46 (t, [2-[2-[2-[2-(2- J = 5.6 Hz,1H), 8.16 (s, 1H), 8.01 (t, aminoethoxy)- J = 5.2 Hz, 1H), 7.91 (d, J =5.6 Hz, ethoxy]- 1H), 7.84-7.78 (m, 1H), 7.75 (s, 1H), ethoxy]ethoxy]-7.49 (d, J = 7.2 Hz, 1H), 7.44 (d, J = ethyl]carbamate 5.6 Hz, 1H), 7.39(d, J = 8.4 Hz, 1H), (CAS# 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 4.99-01187-40-0) 4.82 (m, 1H), 4.79 (s, 2H), 4.54 (dd, J = 3.2, 11.2 Hz, 1H),4.26 (dd, J = 6.4, 11.2 Hz, 1H), 4.10-4.08 (m, 1H), 3.97 (s, 3H),3.60-3.43 (m, 18H), 3.32-3.27 (m, 2H), 2.96-2.84 (m, 1H), 2.70-2.57 (m,3H), 2.09-2.00 (m, 1H), 1.66-1.55 (m, 2H), 1.02 (t, J = 7.2 Hz, 3H) 104I-104 CG CN 998.1 11.11 (s, 1H), 11.02 (s, 1H), 9.04 (d, J = 4.0 Hz,2H), 8.55 (s, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.13 (s, 1H), 8.10 (d, J =8.4 Hz, 2H), 8.04-7.89 (m, 3H), 7.86- 7.75 (m, 2H), 7.69 (t, J = 6.0 Hz,1H), 7.50 (d, J = 7.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H),7.19 (d, J = 5.2 Hz, 1H), 5.12 (dd, J = 5.6, 12.8 Hz, 1H), 4.83-4.73 (m,2H), 4.32-4.19 (m, 2H), 3.29-3.26 (m, 2H), 3.14 (d, J = 6.0 Hz, 2H),2.89 (d, J = 9.2 Hz, 1H), 2.64- 2.56 (m, 2H), 2.11-1.98 (m, 1H), 1.61-1.37 (m, 4H), 1.31-1.21 (m, 14H) Variations in reaction time for Method8 were as follows: Step 1 was run anywhere from 0.5-16 h, Step 2anywhere from 0.5-3 h, Step 3 anywhere from 0.5-12 h.

Further Examples Using Synthetic Methods Similar to Method 8 Example105:N-[3-carbamoyl-1-[4-[2-[2-[2-[2-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]ethoxy]ethoxy]ethoxy]ethoxymethyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-105

To a mixture of tert-butylN-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethyl]carbamate (31.0 mg, 106umol, synthesized via Steps 1-3 of Intermediate AO) in THF (15 mL) wasadded Na metal (6.00 mg, 267 umol) andN-[1-[4-(bromomethyl)phenyl]-3-carbamoyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(60.0 mg, 106 umol, Intermediate CV). The mixture was stirred at rt for18 hours. On completion, the mixture was concentrated in vacuo. Theresidue was purified by reverse phase chromatography (0.1% FA in water)to give the tert-butylN-[2-[2-[2-[2-[[4-[3-carbamoyl-4-[[2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-pyrazol-1-yl]phenyl]methoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamatecompound (15.0 mg, 18% yield) as a white solid. LC-MS (ESI⁺) m/z 799.4(M+Na)⁺.

Steps 2 & 3 followed Method 8 as described above where the deprotectionwas run at rt for 30 min. Intermediate CA was used as the acid couplingpartner in the last step, where the reaction was run at rt for 18 h. Thefinal product was purified by Pre-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 30%-60%, 10min) to give the title compound I-105 (1.20 mg, 6% yield) as whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 10.99 (s, 1H), 9.01(s, 1H), 8.93 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.11-7.86 (m, 4H),7.83-7.76 (m, 1H), 7.74-7.64 (m, 2H), 7.50-7.47 (m, 3H), 7.42-7.34 (m,2H), 7.27 (s, 1H), 7.18 (d, J=5.2 Hz, 1H), 5.11 (dd, J=5.2, 12.8 Hz,1H), 4.78 (s, 2H), 4.55 (s, 2H), 4.31-4.19 (m, 2H), 3.61-3.38 (m, 16H),2.95-2.88 (m, 1H), 2.61-2.58 (m, 2H), 2.06-2.03 (m, 1H); LC-MS (ESI⁺)m/z 1013.3 (M+Na)⁺.

Example 106 (Method 9):N-[3-carbamoyl-1-[4-[5-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]pentylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-106

Step 1—Tert-ButylN-[5-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxacetyl]amino]pentyl]carbamate

To a mixture of tert-butyl N-(5-aminopentyl)carbamate (1.50 g, 7.41mmol, CAS #51644-96-3) and DIPEA (3.83 g, 29.6 mmol) in DMF (15 mL) wasadded 2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyaceticacid (2.46 g, 7.41 mmol, Intermediate CA) and HATU (3.38 g, 8.90 mmol).The reaction mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byprep-HPLC (0.1% NH₃ H₂O) to give the title compound (2.10 g, 54% yield)as a white solid. LC-MS (ESI⁺) m/z 417.0 (M+H−100)⁺.

Step2—N-(5-aminopentyl)-2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxy-acetamide

To a mixture of tert-butylN-[5-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]pentyl]carbamate (500 mg, 967 umol) in DCM (4 mL) was added HCl indioxane (4 M, 2 mL). The reaction mixture was stirred at rt for 0.5hour. On completion, the reaction mixture was concentrated in vacuo. Theresidue was purified by prep-HPLC (0.1% NH₃ H₂O) to give the titlecompound (400 mg, 99% yield) as white solid. LC-MS (ESI⁺) m/z 417.1(M+H)⁺.

Step 3—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[5-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]pentylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a mixture ofN-(5-aminopentyl)-2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxy-acetamide(250 mg, 552 umol, HCl) and DIPEA (356 mg, 2.76 mmol) in DMF (4 mL) wasadded4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (339 mg, 552 umol, Intermediate CN) and HATU (251 mg, 662 umol).The reaction mixture was stirred at rt for 0.5 hour. On completion, thereaction mixture was diluted with water (5 mL) and filtered andconcentrated in vacuo to give the title compound (400 mg, 80% yield) aslight yellow solid. LC-MS (ESI⁺) m/z 1014.3 (M+H)⁺.

Step4—N-[3-carbamoyl-1-[4-[5-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]pentylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[5-[[2-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxyacetyl]amino]pentylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(400 mg, 394 umol) in DCM (3 mL) was added HCl in dioxane (4 M, 2 mL).The reaction mixture was stirred at rt for 0.5 hour. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byprep-HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobile phase:[water (0.225% FA)-ACN]) to give the title compound I-106 (79.4 mg, 20%yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 11.03(s, 1H), 9.04 (s, 2H), 8.56 (t, J=5.6 Hz, 1H), 8.26 (d, J=5.2 Hz, 1H),8.15 (s, 1H), 8.12-8.08 (m, 2H), 8.04-7.94 (m, 3H), 7.85-7.76 (m, 2H),7.71 (t, J=6.4 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H),7.28 (s, 1H), 7.21-7.16 (m, 1H), 5.14 (dd, J=5.2, 12.8 Hz, 1H), 4.81 (s,2H), 4.29-4.21 (m, 2H), 3.30-3.27 (m, 2H), 3.18 (d, J=6.0 Hz, 2H),2.96-2.86 (m, 1H), 2.66-2.61 (m, 1H), 2.60-2.56 (m, 1H), 2.10-2.01 (m,1H), 1.60-1.46 (m, 4H), 1.40-1.29 (m, 2H); LC-MS (ESI⁺) m/z 914.3 (M+H)+

TABLE 7 Compounds synthesized via Method 9 with the coupling of variousamines and acids in Step 1, followed by coupling with acid IntermediateCN in Step 3 LCMS Step 1 Step 1 (ES+) Intermediate Intermediate m/z Ex-#I-# Amine Acid (M + H)⁺ HNMR (400 MHz, DMSO-d6) δ 107 I-107 CI CH 1161.211.01 (s, 1H), 9.07-8.99 (m, 2H), 8.96 (s, 1H), 8.74-8.56 (m, 2H), 8.26(d, J = 5.6 Hz, 1H), 8.15 (s, 1H), 8.12-8.06 (m, 2H), 8.05-7.99 (m, 2H),7.78 (s, 1H), 7.72- 7.64 (m, 1H), 7.47-7.35 (m, 5H), 7.26 (s, 1H), 7.19(d, J = 5.4 Hz, 1H), 5.21 (s, 1H), 4.56 (d, J = 9.6 Hz, 1H), 4.48-4.33(m, 3H), 4.31-4.17 (m, 3H), 4.00-3.90 (m, 2H), 3.71-3.53 (m, 18H), 2.43(s, 3H), 2.11-2.02 (m, 1H), 1.96-1.86 (m, 1H), 0.96-0.89 (m, 9H) 108I-108 tert-butyl N- CA 1026.3ª 11.12 (br s, 1H), 11.01 (s, 1H), 9.04 (d,J = [2-[2-[2-(2- 4.0 Hz, 2H), 8.65 (t, J = 5.2 Hz, 1H), aminoethoxy)-8.27 (d, J = 5.2 Hz, 1H), 8.19-8.07 (m, ethoxy]ethoxy 3H), 8.06-7.97 (m,3H), 7.85-7.75 (m, 1- 2H), 7.70 (t, J = 6.4 Hz, 1H), 7.49 (d, J =ethyl]carbama 7.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.28 te (CAS# (s,1H), 7.19 (d, J = 5.2 Hz, 1H), 5.19- 101187-40-0) 5.05 (m, 1H), 4.78 (s,2H), 4.35-4.17 (m, 2H), 3.59-3.49 (m, 12H), 3.48-3.45 (m, 4H), 2.97-2.83(m, 1H), 2.66-2.61 (m, 1H), 2.60-2.56 (m, 1H), 2.07-2.00 (m, 1H) 109I-109 tert-butyl N- CA  956.4 11.12 (s, 1H), 11.01 (s, 1H), 9.03 (d, J =(8- 4.8 Hz, 2H), 8.55 (t, J = 5.6 Hz, 1H), 8.26 aminooctyl)- (d, J = 5.6Hz, 1H), 8.14 (s, 1H), 8.12- carbamate 8.07 (m, 2H), 8.05-7.98 (m, 2H),7.93 (t, (CAS# 88829- J = 5.6 Hz, 1H), 7.85-7.79 (m, 1H), 7.77 82-7) (s,1H), 7.69 (t, J = 6.4 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.40 (d, J =8.4 Hz, 1H), 7.27 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 5.14-5.08 (m, 1H),4.77 (s, 2H), 4.30-4.20 (m, 2H), 3.29-3.22 (m, 2H), 3.18-3.11 (m, 2H),2.96-2.85 (m, 1H), 2.64-2.56 (m, 2H), 2.08-2.01 (m, 1H), 1.60-1.38 (m,4H), 1.29 (s, 8H) 110 I-110 tert-butyl N- CA  915.9 11.12 (s, 1H), 11.03(s, 1H), 9.05 (s, 1H), [2-(2- 9.03 (s, 1H), 8.60 (t, J = 5.2 Hz, 1H),8.27 aminoethoxy)- (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 8.09-ethyl]carbamate 8.05 (m, 2H), 8.05-7.98 (m, 3H), 7.83- (CAS# 7.76 (m,2H), 7.71 (t, J = 6.4 Hz, 1H), 127828-22-2) 7.47 (d, J = 7.2 Hz, 1H),7.39 (d, J = 8.8 Hz, 1H), 7.28 (s, 1H), 7.19 (dd, J = 1.6, 5.2 Hz, 1H),5.15-5.12 (m, 1H), 4.79 (s, 2H), 4.31-4.20 (m, 2H), 3.61-3.56 (m, 2H),3.55-3.51 (m, 2H), 3.50-3.44 (m, 2H), 3.40-3.37 (m, 2H), 2.95-2.84 (m,1H), 2.64-2.55 (m, 2H), 2.10-2.01 (m, 1H) 111 I-111 tert-butyl N- CA 900.3 11.12 (s, 1H), 11.02 (s, 1H), 9.04 (d, J = (4- 4.0 Hz, 2H), 8.59(t, J = 5.6 Hz, 1H), 8.26 aminobutyl)- (d, J = 5.2 Hz, 1H), 8.15-8.08(m, 3H), carbamate 8.02 (m, 3H), 7.85-7.80 (m, 1H), 7.78 (s, (CAS#68076- 1H), 7.70 (t, J = 6.8 Hz, 1H), 7.49 (d, J = 36-8) 7.2 Hz, 1H),7.40 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 7.21-7.17 (m, 1H), 5.12 (dd, J =5.6, 13.2 Hz, 1H), 4.79 (s, 2H), 4.31-4.20 (m, 2H), 3.30-3.26 (m, 2H),3.24-3.18 (m, 2H), 2.95-2.84 (m, 1H), 2.64-2.54 (m, 2H), 2.07-2.00 (m,1H), 1.53 (m, 4H) 112 I-112 tert-butyl N- CA  886.5 11.12 (s, 1H), 11.02(s, 1H), 9.04 (d, J = 2 (3- Hz, 2H), 8.59 (t, J = 6 Hz, 1H), 8.26 (d,aminopropyl)- J = 5.2 Hz, 1H), 8.17-8.07 (m, 3H), 8.07- carbamate 7.98(m, 3H), 7.83 (dd, J = 7.2, 8.4 Hz, (CAS# 75178- 1H), 7.78 (s, 1H), 7.70(t, J = 6.4 Hz, 1H), 96-0) 7.50 (d, J = 7.2 Hz, 1H), 7.42 (d, J = 8.4Hz, 1H), 7.28 (s, 1H), 7.19 (dd, J = 1.6, 5.2 Hz, 1H), 5.13 (dd, J =5.2, 12.8 Hz, 1H), 4.80 (s, 2H), 4.31-4.19 (m, 2H), 3.27 (m, 2H), 3.25(m, 2H), 2.98-2.84 (m, 1H), 2.65-2.54 (m, 2H), 2.09-2.00 (m, 1H),1.78-1.68 (m, 2H) 113 I-113 DH CH 1071.3 11.03 (s, 1H), 9.05 (d, J = 3.2Hz, 2H), 8.65 (t, J = 5.2 Hz, 1H), 8.31 (t, J = 6.4 Hz, 1H), 8.26 (d, J= 5.2 Hz, 1H), 8.15 (s, 1H), 8.13-8.08 (m, 3H), 8.06-8.00 (m, 2H), 7.78(br s, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.34 (d,J = 8.0 Hz, 2H), 7.28 (s, 1H), 7.19 (dd, J = 1.2, 5.2 Hz, 1H), 6.72 (d,J = 7.6 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 4.34 (d, J = 6.0 Hz, 2H),4.30-4.20 (m, 2H), 3.95 (s, 2H), 3.62-3.40 (m, 16H), 2.56-2.54 (m, 3H)114 I-114 DH DI 1115.8 11.03 (s, 1H), 9.05 (d, J = 3.2 Hz, 2H), 8.65 (brt, J = 5.2 Hz, 1H), 8.31 (br t, J = 6.4 Hz, 1H), 8.26 (d, J = 5.2 Hz,1H), 8.14 (br s, 1H), 8.13-8.08 (m, 3H), 8.06-8.01 (m, 2H), 7.78 (br s,1H), 7.71 (br t, J = 6.3 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.35 (d, J =8.4 Hz, 2H), 7.28 (s, 1H), 7.21-7.16 (m, 1H), 6.72 (d, J = 7.6 Hz, 1H),6.61 (d, J = 7.6 Hz, 1H), 4.34 (br d, J = 6.0 Hz, 2H), 4.30-4.20 (m,2H), 3.95 (s, 2H), 3.62-3.41 (m, 20H), 2.54-2.53 (s, 3H) 115 I-115 CI DM1117.4 11.02 (s, 1H), 9.04 (d, J = 4.0 Hz, 2H), 8.97 (s, 1H), 8.64 (t, J= 5.2 Hz, 1H), 8.59 (t, J = 6.0 Hz, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.13(s, 1H), 8.11-8.08 (m, 2H), 8.05-8.01 (m, 2H), 7.77 (s, 1H), 7.70 (t, J= 6.4 Hz, 1H), 7.47-7.36 (m, 5H), 7.28 (s, 1H), 7.18 (dd, J = 1.2, 5.2Hz, 1H), 5.16 (s, 1H), 4.57 (d, J = 9.6 Hz, 1H), 4.49-4.34 (m, 3H),4.31-4.23 (m, 3H), 3.97 (s, 2H), 3.71-3.65 (m, 1H), 3.61- 3.54 (m, 10H),3.47-3.42 (m, 2H), 2.53 (d, J = 2.0 Hz, 1H), 2.44 (s, 3H), 2.11- 2.02(m, 1H), 1.94-1.87 (m, 1H), 0.96- 0.91 (m, 9H) Variations in reactiontime for Method 9 were as follows: Step 1 was run anywhere from 0.5-12h, Step 3 anywhere from 0.5-12 h, and Step 4 anywhere from 0.5-12 hr.ªmass measured as (M+Na)+.

Further Examples Using Synthetic Methods Similar to Method 9 Example116:N-(3-carbamoyl-1-(4-((2-((5-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)pentyl)oxy)ethyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide,I-116

N-(3-carbamoyl-1-(4-((2-((5-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)ethoxy)pentyl)oxy)ethyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamideI-116 was synthesized via Method 9, by coupling amine Intermediate CFwith acid Intermediate CN in Step 1. Step 2 was not performed as theamine did not have a BOC group for deprotection. In Step 3, IntermediateCA was employed as the acid for the coupling. Characterization of thefinal product: ¹H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 11.00 (s, 1H),9.02 (d, J=8.4 Hz, 2H), 8.64 (t, J=5.2 Hz, 1H), 8.26 (d, J=5.2 Hz, 1H),8.14 (s, 1H), 8.11-8.06 (m, 2H), 8.05-8.00 (m, 2H), 7.97 (t, J=6.4 Hz,1H), 7.82-7.75 (m, 2H), 7.69 (t, J=6.4 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H),7.38 (d, J=8.4 Hz, 1H), 7.26 (s, 1H), 7.20-7.16 (m, 1H), 5.10 (dd,J=5.2, 12.8 Hz, 1H), 4.78 (s, 2H), 4.30-4.18 (m, 2H), 3.40-3.28 (m,12H), 2.94-2.84 (m, 1H), 2.65-2.60 (m, 1H), 2.52-2.44 (m, 1H), 2.08-2.02(m, 1H), 1.53-1.44 (m, 4H), 1.35-1.27 (m, 2H). LC-MS (ESI⁺) m/z 1002.4(M+H)⁺.

Example 117:N-(3-carbamoyl-1-(4-((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide,I-117

Tert-Butyl(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)carbamate was synthesized in Step 1 as follows: To a mixture of3-(4-amino-1-oxo-isoindolin-2-yl)piperidine-2,6-dione (0.10 g, 385 umol,CAS #191732-72-6) in DMA (2 mL) was added2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethyl methanesulfonate(151 mg, 462 umol, synthesized via Step 1 of Intermediate A1), NaI (17.3mg, 115 umol) and DIPEA (149 mg, 1.16 mmol, 201 uL). Then the reactionmixture was stirred at 80° C. for 2 hours. On completion, the reactionmixture was concentrated in vacuo. The residue was purified by prep-TLC(PE:EA=0:1) to give the title compound I-117 (0.18 g, 50% purity, 47%yield) as a yellowish solid (LC-MS (ESI⁺) m/z 513.1 (M+Na)⁺).

Steps 2-4 followed Method 9, where Intermediate CN was used as the acidin Step 3 which was coupled with the amine at rt for 12 hours.Characterization of the final product: ¹H NMR (400 MHz, DMSO-d₆) δ11.13-10.90 (m, 2H), 9.04 (s, 2H), 8.65 (t, J=5.2 Hz, 1H), 8.26 (d,J=5.2 Hz, 1H), 8.16-8.07 (m, 3H), 8.05-7.99 (m, 2H), 7.78 (s, 1H), 7.70(t, J=6.4 Hz, 1H), 7.32-7.24 (m, 2H), 7.19 (dd, J=1.2, 5.2 Hz, 1H), 6.94(d, J=7.2 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 5.58 (s, 1H), 5.11 (dd,J=5.2, 13.2 Hz, 1H), 4.29-4.11 (m, 4H), 3.77-3.52 (m, 8H), 3.49-3.41 (m,4H), 2.97-2.87 (m, 1H), 2.64-2.59 (m, 2H), 2.05-2.03 (m, 1H). LC-MS(ESI⁺) m/z 888.1 (M+H)⁺.

Example 118 (Method 10):[2-[2-[[(1S)-1-[(4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-methyl-butyl]pyridine-3-carboxamide,I-118

Step 1—Ethyl2-[2-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-1,1-dimethylpropoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of ethyl2-[2-[2-[2-[2-(3-amino-2-fluoro-1,1-dimethyl-propoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (200 mg, 521 umol, Intermediate BJ) and DIPEA (337 mg,2.61 mmol) in DMF (3 mL) was added6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxylicacid (271 mg, 625 umol, Intermediate L as the TFA salt) and HATU (257mg, 678 umol). The reaction mixture was stirred at rt for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% FA) to give the title compound (80.0 mg,22% yield) as a red oil. LC-MS (ESI⁺) m/z 686.6 (M+H)⁺.

Step2—2-[2-[2-[2-[2-[3-[[6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a mixture of ethyl2-[2-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate(70.0 mg, 102 umol) in THF (4 mL) and MeOH (1 mL) was added a solutionof LiOH (4.89 mg, 204 umol) in H₂O (1 mL). The reaction mixture wasstirred at rt for 0.5 hour. On completion, the reaction mixture wasacidified with HCl (1 N) until the pH=5-6, then concentrated in vacuo togive a residue. The residue was purified by prep-HPLC (column:Phenomenex Synergi C18 150*30 mm*4 um; mobile phase: [water (0.05%HCl)-ACN]) to give the title compound (20.0 mg, 29% yield) as a lightyellow oil. LC-MS (ESI⁺) m/z 658.1 (M+H)⁺.

Step3—6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-[2-fluoro-3-[2-[2-[2-[2-[2-[[(1S)-1-[(4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-methyl-butyl]pyridine-3-carboxamide

To a mixture of(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(21.3 mg, 45.6 umol, Intermediate CI, as the HCl salt) and DIPEA (29.4mg, 228 umol) in DMF (3 mL) was added2-[2-[2-[2-[2-[3-[[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carbonyl]amino]-2-fluoro-1,1-dimethyl-propoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticacid (30.0 mg, 45.6 umol) and HATU (20.8 mg, 54.7 umol). The reactionmixture was stirred at rt for 0.5 hour. On completion, the reactionmixture was concentrated in vacuo. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]) to give the title compound I-118 (10.9 mg, 21% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s, 1H), 9.03 (d,J=2.0 Hz, 1H), 8.98 (s, 1H), 8.87 (t, J=5.2 Hz, 1H), 8.72-8.58 (m, 4H),7.76 (s, 1H), 7.49-7.34 (m, 5H), 4.57 (d, J=9.6 Hz, 1H), 4.48-4.43 (m,1H), 4.43-4.37 (m, 1H), 4.35 (s, 1H), 4.30-4.21 (m, 1H), 3.97 (s, 2H),3.66-3.50 (m, 20H), 2.59 (s, 1H), 2.54-2.53 (m, 1H), 2.44 (s, 3H),2.10-2.01 (m, 1H), 1.93-1.87 (m, 1H), 1.21 (s, 6H), 0.94 (s, 9H),0.89-0.84 (m, 2H), 0.58 (d, J=2.0 Hz, 2H). LC-MS (ESI⁺) m/z 1070.1(M+H)⁺.

TABLE 8 Compounds synthesized via Method 10 with the coupling of variousacids and amines in Step 1, followed by coupling with an amine in Step3. LCMS Step 1 Step 1 Step 3 (ES+) Intermediate IntermediateIntermediate m/z HNMR (400 MHz, Ex-# I-# Amine Acid Amine (M + H)⁺DMSO-d6) δ 119 I-119 BW N CI 1087.6 10.38 (s, 1H), 9.06 (s, 1H), 8.99(s, 1H), 8.63- 8.52 (m, 5H), 8.47 (s, 1H), 8.31 (s, 1H), 8.28 (d, J =9.2 Hz, 1H), 7.57 (d, J = 5.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H),7.46-7.37 (m, 5H), 4.84-4.68 (m, 1H), 4.57 (d, J = 9.6 Hz, 1H),4.48-4.43 (m, 1H), 4.42-4.37 (m, 1H), 4.36 (s, 1H), 4.29-4.22 (m, 1H),3.97 (s, 2H), 3.56- 3.48 (m, 24H), 2.62 (s, 2H), 2.46-2.45 (m, 1H), 2.44(s, 3H), 2.09-2.02 (m, 1H), 1.96-1.85 (m, 1H), 0.95 (s, 9H), 0.93 (s,2H), 0.59 (s, 2H) 120 I-120 BX N CI  955.5 10.4 ( s, 1H), 9.06 (s, 1H),8.97 (s, 1H), 8.63-8.52 (m, 3H), 8.47 (s, 1H), 8.27 (d, J = 8.8 Hz, 1H),7.57 (d, J = 6.0 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.45 ( d, J = 9.6Hz, 1H), 7.40 (s, 4H), 4.85-4.65 (m, 1H), 4.57 (d, J = 9.6 Hz, 1H),4.48-4.37 (m, 2H), 4.36 (s, 1H), 4.30-4.23 (m, 1H), 3.98 (s, 2H), 3.73-3.52 (m, 15H), 3.32-3.25 (m, 1H), 2.69-2.65 (m, 1H), 2.71-2.60 (m, 1H),2.43(s, 3H), 2.05 (m, 1H), 1.90 (m, 1H), 0.98-0.92 (m, 11H), 0.59 (s,2H) 121 I-121 BL L CI 1056.6 9.06 (d, J = 2.0 Hz, 1H), 9.02 (d, J = 2.0Hz, 1H), 8.98 (s, 1H), 8.86-8.80 (m, 1H), 8.66 (s, 1H), 8.63 (s, 1H),8.62-8.55 (m, 2H), 7.72 (s, 1H), 7.45- 7.38 (m, 5H), 5.20-5.15 (m, 1H),4.70-4.61 (m, 1H), 4.56-4.5 (m, 1H), 4.47-4.33 (m, 3H), 4.29- 4.21 (m,1H), 3.96 (s, 2H), 3.72-3.48 (m, 16H), 2.62- 2.57 (m, 1H), 2.55-2.52 (m,4H), 2.43 (s, 3H), 2.07- 2.00 (m, 1H), 1.94-1.86 (m, 1H), 1.27-1.22 (m,1H), 1.19-1.14 (m, 3H), 0.94 (s, 9H), 0.88-0.84 (m, 2H), 0.59-0.54 (m,122ª I-122 BM L CI  968.1 2H) 9.05 (s, 1H), 9.01 (d, J = 2.0 Hz, 1H),8.96 (s, 1H), 8.83 (d, J = 5.6 Hz, 1H), 8.66 (s, 1H), 8.65-8.53 (m, 3H),7.72 (s, 1H), 7.46- 7.36 (m, 5H), 5.19 (s, 1H), 4.69-4.61 (m, 1H),4.69-4.61 (m, 1H), 4.59- 4.50 (m, 2H), 4.49-4.40 (m, 2H), 4.39-4.33 (m,2H), 4.29- 4.22 (m, 1H), 3.98 (s, 2H), 3.63-3.60 (m, 10H), 2.59-2.56 (m,2H), 2.43 (s, 3H), 2.10- 2.02 (m, 1H), 1.92-1.90 (m, 1H), 1.17-1.11 (m,3H), 0.94 (s, 9H), 0.89- 0.83 (m, 2H), 0.56 (s, 2H) 123 I-123 CI DT DR1150.6 8.98 (s, 1H), 8.60 (br t, J = 6.0 Hz, 1H), 8.52 (s, 1H),7.45-7.39 (m, 5H), 7.19- 7.16 (m, 1H), 7.13-7.10 (m, 1H), 5.48-5.42 (m,1H), 5.21-5.11 (m, 2H), 4.60-4.54 (m, 1H), 4.48- 4.38 (m, 2H), 4.37-4.34(m, 1H), 4.28-4.23 (m, 1H), 4.16-4.10 (m, 2H), 3.97 (s, 2H), 3.94-3.90(m, 1H), 3.69-3.66 (m, 1H), 3.63-3.53 (m, 16H), 3.49 (s, 7H), 3.06-3.00(m, 1H), 2.95-2.88 (m, 1H), 2.61-2.54 (m, 2H), 2.44 (s, 3H), 2.42-2.38(m, 3H), 2.37-2.02 (m, 4H), 1.95-1.89 (m, 1H), 1.88-1.81 (m, 2H), 1.71-1.35 (m, 6H), 0.94 (s, 9H) Variations in reaction time for Method 10were as follows: Step 1 was run anywhere from 0.5-12 h, Step 2 anywherefrom 0.5-3.5 h, and Step 3 anywhere from 0.5-3 hr. ªProduct isolated asthe FA salt.

Further Examples Using Synthetic Methods Similar to Method 10 Example124:(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[2-[4-[4-[[(8R)-8-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide,I-124

Ethyl2-[2-[2-[2-[2-[2-[4-[4-[[(8R)-8-[(2S)-3-amino-2-hydroxy-3-oxo-propyl]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-1-yl]oxy]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetatewas synthesized as follows: to a solution of(2S)-2-hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide (90.0 mg, 187 umol,Intermediate DR) in DMF (5 mL) was added K₂CO₃ (129 mg, 933 umol) andethyl2-[2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate(113 mg, 280 umol, synthesized via Steps 1-2 of Intermediate BW). Thereaction mixture was stirred at 60° C. for 25 h. On completion, thereaction mixture was concentrated in vacuo to give the title compound(130 mg, 92% yield) as a yellow solid (LC-MS (ESI⁺) m/z 752.4 (M+H)⁺).The final product was then synthesized via Steps 2-3 of Method 10, whereStep 2 was run for 15 h at rt and Step 3 was run for 3 h at rt usingacid Intermediate CI. Characterization of the final product I-124: ¹HNMR (400 MHz, DMSO-d₆) δ 8.98 (s, 1H), 8.60 (t, J=6.0 Hz, 1H), 8.52 (s,1H), 8.22 (s, 1H), 7.42 (d, J=9.6 Hz, 2H), 7.39 (s, 2H), 7.15 (s, 1H),7.11 (s, 1H), 5.18-5.12 (m, 1H), 4.57 (d, J=9.6 Hz, 1H), 4.47-4.40 (m,2H), 4.40-4.33 (m, 2H), 4.25 (dd, J=5.6, 15.8 Hz, 2H), 3.97 (s, 2H),3.95-3.90 (m, 2H), 3.68-3.48 (m, 20H), 3.05-2.98 (m, 1H), 2.94-2.87 (m,1H), 2.61-2.53 (m, 2H), 2.44 (s, 12H), 2.16-2.04 (m, 3H), 1.92-1.83 (m,3H), 1.69-1.58 (m, 2H), 1.57-1.41 (m, 2H), 1.41-1.32 (m, 2H), 0.94 (s,9H); LC-MS (ESI⁺) m/z 1136.1 (M+H)⁺.

Example 125:N-[3-carbamoyl-1-[4-[8-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]octylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-125

Tert-butyl2-[8-[[4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoyl]amino]octoxy]acetatewas synthesized via Method 10, Step1, where amine Intermediate DX andacid Intermediate CN were coupled at rt for 2 hours. In Step 2, the Bocgroups were removed as follows: to a solution of tert-butyl2-[8-[[4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoyl]amino]octoxy]acetate(120 mg, 134 umol) in DCM (3 mL) was added TFA (760 mg, 6.75 mmol). Themixture was stirred at rt for 3 hours. On completion, the reactionmixture was concentrated in vacuo to give the title compound (110 mg,100% yield, TFA salt) as light yellow oil (LC-MS (ESI⁺) m/z 701.4(M+H)). The third step followed Method 10, where amine Intermediate CIwas coupled with the acid at rt for 3 hours. Characterization of thefinal product I-125: ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.04 (d,J=2.0 Hz, 2H), 8.97 (s, 1H), 8.61 (t, J 6.0 Hz, 1H), 8.54 (t, J 6.0 Hz,1H), 8.25 (d, J=5.6 Hz, 1H), 8.13 (s, 1H), 8.08 (d, J=8.8 Hz, 2H), 8.02(d, J=8.8 Hz, 2H), 7.77 (s, 1H), 7.70 (t, J=6.4 Hz, 1H), 7.47-7.31 (m,5H), 7.27 (s, 1H), 7.20-7.16 (m, 1H), 5.16 (d, J=3.6 Hz, 1H), 4.56 (d,J=9.6 Hz, 1H), 4.48-4.32 (m, 3H), 4.29-4.19 (m, 3H), 3.91 (s, 2H),3.71-3.57 (m, 2H), 3.49-3.44 (m, 2H), 3.29-3.21 (m, 2H), 2.43 (s, 3H),2.11-2.01 (m, 1H), 1.95-1.84 (m, 1H), 1.59-1.47 (m, 4H), 1.36-1.23 (m,8H), 0.93 (s, 9H); LC-MS (ESI⁺) m/z 1113.5 (M+H)⁺.

Example 126:4-[2-[4-[2-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]ethynyl]-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide,I-126

Step1—4-bromo-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carbonitrile

To a solution of1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carbonitrile(200 mg, 582 umol, Intermediate CD) in ACN (7.00 mL) was added NBS (228mg, 1.28 mmol), and the mixture was stirred at 60° C. for 2 hours. Oncompletion, the mixture was concentrated in vacuo. The mixture waspurified by prep-TLC (EA) to give the title compound (130 mg, 52% yield)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 8.06 (s, 1H),7.68 (s, 1H), 7.57 (s, 1H), 4.99-4.79 (m, 1H), 4.71 (d, J=11.6 Hz, 1H),4.41-4.32 (m, 1H), 4.21-4.14 (m, 1H), 4.07 (s, 3H), 2.70-2.47 (m, 1H),1.86-1.66 (m, 2H), 1.13 (t, J=7.2 Hz, 3H).

Step2—4-Bromo-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide

To a solution of4-bromo-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carbonitrile(300 mg, 710 umol) in DMSO (3.00 mL) was added K₂CO₃ (39.2 mg, 284 umol)and H₂O₂ (241 mg, 2.13 mmol, 30% solution). The mixture was stirred atrt for 16 hours. On completion, the mixture was diluted with H₂O (30 mL)and extracted with EA (3×30 mL). The organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (300 mg, 80% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.88 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.85 (s, 1H),7.80 (s, 1H), 5.00-4.82 (m, 1H), 4.56-4.50 (m, 1H), 4.30-4.23 (m, 1H),4.10 (s, 1H), 4.00 (s, 3H), 1.64-1.53 (m, 2H), 1.02 (t, J=7.2 Hz, 3H).

Step 3—Methyl4-[2-[6-carbamoyl-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-4-isoquinolyl]ethynyl]benzoate

4-bromo-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide(100 mg, 227 umol), Pd(PPh₃)₂Cl₂ (15.9 mg, 22.7 umol) and CuI (8.65 mg,45.4 umol) were placed in a microwave tube. Then methyl4-ethynylbenzoate (72.7 mg, 454 umol, CAS #10602-03-6), TEA (229 mg,2.27 mmol) and DMF (2.00 mL) were added into the above tube. The mixturewas degassed with nitrogen for 5 minutes. The sealed tube was heated at120° C. for 3 hours under microwave. On completion, the mixture wasconcentrated in vacuo. The mixture was purified by reverse phasechromatography (0.1% FA) to give the title compound (40.0 mg, 33% yield)as a black solid. LC-MS (ESI⁺) m/z 520.3 (M+H)⁺.

Step4—4-[2-[6-Carbamoyl-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-4-isoquinolyl]ethynyl]benzoicAcid

To a solution of methyl4-[2-[6-carbamoyl-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-4-isoquinolyl]ethynyl]benzoate (40.0 mg, 76.9 umol)in a mixed solvent of THF (3.00 mL), MeOH (1.00 mL) and H₂O (1.00 mL)was added LiOH (9.22 mg, 384 umol). The mixture was stirred at rt for 16hours. On completion, the mixture was acidified with 1N HCl solutionuntil the pH=5. The mixture was concentrated in vacuo to give the titlecompound (38.0 mg, 85% yield) as a black solid. LC-MS (ESI⁺) m/z 506.2(M+H)⁺.

Step5—4-[2-[4-[2-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]ethynyl]-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide

To a solution of4-[2-[6-carbamoyl-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-4-isoquinolyl]ethynyl]benzoicacid (28.0 mg, 55.3 umol) and 4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (26.8mg, 55.3 umol, HCl, synthesized via Steps 1-2 of Example 128) in DMF(2.00 mL) was added HATU (25.2 mg, 66.4 umol) and DIPEA (28.6 mg, 221umol). The mixture was stirred at rt for 30 minutes. On completion, themixture was quenched with H₂O (2 mL), and the mixture was concentratedin vacuo. The mixture was purified by prep-HPLC (column: Boston GreenODS 150*30 5 u; mobile phase: [water (0.225% FA)-ACN]; B %: 37%-67%, 10min) to give the title compound I-126 (13.3 mg, 25% yield) as yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.91 (s, 1H), 8.65 (t,J=5.2 Hz, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 7.95 (s, 2H), 7.93 (s, 1H),7.82 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.71 (s, 1H), 7.60-7.54 (m,1H), 7.13 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.60 (t, J=5.6 Hz,1H), 5.09-5.02 (m, 1H), 5.01-4.84 (m, 1H), 4.63-4.57 (m, 1H), 4.35-4.28(m, 1H), 4.16-4.09 (m, 1H), 4.00 (s, 3H), 3.63-3.59 (m, 2H), 3.56-3.44(m, 14H), 2.89-2.85 (m, 1H), 2.63-2.61 (m, 1H), 2.58-2.58 (m, 1H),2.57-2.56 (m, 1H), 2.05-2.00 (m, 1H), 1.65-1.58 (m, 2H), 1.03 (t, J=7.2Hz, 3H); LC-MS (ESI⁺) m/z 936.2 (M+H)⁺.

Example 127 (Method 11):N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-127

Step 1—Tert-Butyln-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]carbamate

A solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate(2.50 g, 10.1 mmol, CAS #153086-78-3),2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (3.34 g, 12.1mmol, Intermediate R) and diisopropyl ethylamine (2.60 g, 20.1 mmol) indioxane (120 mL) was stirred at 115° C. for 16 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was purified bycolumn chromatography (petroleum ether:ethyl acetate=1:1) to give thetitle compound (2.10 g, 40% yield) as a yellow gum. ¹H NMR (400 MHz,CDCl₃) δ 8.50 (s, 1H), 7.54-7.48 (m, 1H), 7.12 (d, J=7.2 Hz, 1H), 6.92(d, J=8.4 Hz, 1H), 6.59-6.48 (m, 1H), 5.15-5.00 (m, 1H), 4.95-4.85 (m,1H), 3.79-3.71 (m, 2H), 3.70-3.62 (m, 4H), 3.60-3.54 (m, 2H), 3.52-3.45(m, 2H), 3.35-3.25 (m, 2H), 2.92-2.71 (m, 3H), 2.19-2.09 (m, 1H), 1.44(s, 9H); LC-MS (ESI⁺) m/z 527.1 (M+Na)⁺.

Step2—4-[2-[2-(2-Aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a solution of tert-butylN-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]carbamate (200 mg, 396 umol) in DCM (5 mL) was addedHCl in dioxane (4 M, 5 mL). The reaction mixture was stirred at rt for10 minutes. On completion, the reaction mixture was concentrated invacuo to give the title compound (200 mg, 90% yield) as a yellow solid.LC-MS (ESI⁺) m/z 405.2 (M+H)⁺.

Step 3—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(200 mg, 418 umol) and4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoic acid (257 mg,418 umol, Intermediate CN) in DMF (5 mL) was added DIPEA (270 mg, 2.09mmol, 364 uL). The mixture was stirred at rt for 12 minutes, and thenHATU (191 mg, 502 umol) was added to the mixture. The reaction mixturewas stirred at rt for 12 hours. On completion, the mixture was quenchedwith H₂O (10 mL) and filtered. The filter cake was dried in vacuo togive the title compound (400 mg, 95% yield) as a yellow solid. LC-MS(ESI⁺) m/z 902.2 (M+H−100)⁺.

Step4—N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(400 mg, 399 umol) in DCM (3 mL) was added HCl in dioxane (4 M, 3 mL).The reaction mixture was stirred at rt for 20 minutes. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10 um; mobilephase: [water (0.225% FA)-ACN]; B %: 35 ACN %-63ACN %) to give the titlecompound I-127 (121 mg, 31% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 11.02 (s, 1H), 9.05 (s, 1H), 9.04 (s, 1H),8.63 (t, J=5.2 Hz, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.14 (m, 1H), 8.11-8.06(m, 2H), 8.05-7.99 (m, 2H), 7.79 (m, 2H), 7.56 (dd, J=7.2, 8.4 Hz, 1H),7.29 (s, 1H), 7.19 (dd, J=1.2, 5.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.02(d, J=7.2 Hz, 1H), 6.60 (s, 1H), 5.06 (dd, J=5.6, 13.2 Hz, 1H),4.34-4.20 (m, 2H), 3.67-3.52 (m, 12H), 2.96-2.82 (m, 1H), 2.64-2.58 (m,1H), 2.57-2.55 (m, 1H), 2.13-1.96 (m, 1H); LC-MS (ESI⁺) m/z 902.3 (M+H)⁺

TABLE 9 Compounds synthesized via Method 11 with the addition of variousamines to fluoride Intermediate R in Step 1, followed by coupling withvarious acids in Step 3. LCMS Step 1 Step 3 (ES+) IntermediateIntermediate m/z Ex-# I-# Amine Acid (M + H)⁺ ¹HNMR (400 MHz, DMSO-d6) δ128ª I-128 tert-butyl N-[2-[2- CN 946.5 11.15-11.04 (s, 1H), 11.02 (s,1H), [2-(2- 9.04 (s, 2H), 8.64 (t, J = 5.2 Hz, 1H), aminoethoxy)ethoxy]-8.27 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), ethoxy]ethyl]- 8.12 (s, 1H),8.10 (s, 1H), 8.04 (s, carbamate 1H), 8.02 (s, 1H), 7.78 (s, 1H), 7.71(CAS# 101187-40-0) (t, J = 6.4 Hz, 1H), 7.60-7.55 (m, 1H), 7.28 (s, 1H),7.19 (dd, J = 5.2 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.2Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H), 5.09-5.03 (m, 1H), 4.30- 4.21 (m,2H), 3.63-3.41 (m, 16H), 2.94-2.83 (m, 1H), 2.64-2.55 (m, 2H), 2.07-1.98(m, 1H) 129^(g) I-129 BF L 810.4 11.12 (s, 1H), 9.09 (d, J = 2.0 Hz,1H), 9.05 (d, J = 2.0 Hz, 1H), 8.97 (br s, 1H), 8.70 (s, 1H), 8.65-8.63(m, 2H), 7.79 (s, 1H), 7.59 (dd, J = 7.2, 8.4 Hz, 1H), 7.16 (d, J = 8.4Hz, 1H), 7.05 (d, J = 7.2 Hz, 1H), 6.63 (br s, 1H), 5.06 (dd, J = 5.2,12.8 Hz, 1H), 4.64-4.47 (m, 1H), 3.76-3.70 (m, 10H), 3.44-3.33 (m, 1H),3.24-3.13 (m, 4H), 2.94-2.83 (m, 1H), 2.60- 2.57 (m, 3H), 2.08-1.99 (m,1H), 1.24 (d, J = 3.6 Hz, 6H), 0.92-0.85 (m, 2H), 0.58-0.55 (m, 2H)130^(b) I-130 tert-butyl N-[2-(2- CN 858.0 11.09 (s, 1H), 11.02 (s, 1H),9.04 (d, aminoethoxy)- J = 1.6 Hz, 2H), 8.63 (t, J = 5.2 Hz,ethyl]carbamate 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.15 (s, (CAS# 1H),8.11-8.06 (m, 2H), 8.03-7.97 127828-22-2) (m, 2H), 7.79 (s, 1H), 7.71(t, J = 6.4 Hz, 1H), 7.60-7.54 (m, 1H), 7.28 (s, 1H), 7.21-7.14 (m, 2H),7.02 (d, J = 6.8 Hz, 1H), 6.64 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 5.6,12.8 Hz, 1H), 4.31- 4.19 (m, 2H), 4.12 (s, 2H), 3.70-3.59 (m, 4H),3.52-3.49 (m, 2H), 2.90- 2.83 (m, 1H), 2.63-2.52 (m, 2H), 2.06-1.97 (m,1H) 131^(f) I-131 BD L 854.1 11.10 (s, 1H), 9.14-8.98 (m, 2H), 8.86 (s,1H), 8.65 (d, J = 8.8 Hz, 2H), 8.62-8.58 (m, 1H), 7.72 (s, 1H), 7.56 (t,J = 8.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.07-6.99 (m, 1H), 6.60 (t, J= 5.6 Hz, 1H), 5.05 (dd, J = 5.2, 13.2 Hz, 1H), 4.61-4.42 (m, 1H),3.75-3.59 (m, 14H), 2.95-2.84 (m, 1H),2.82-2.74 (m, 4H), 2.62-2.57 (m,2H), 2.56-2.53 (m, 1H), 2.49- 2.39 (m, 1H), 2.06-1.97 (m, 1H), 1.21 (s,6H), 0.90-0.82 (m, 2H), 0.60- 0.53 (m, 2H) 132^(c) I-132 tert-butylN-(8- CN 898.3 11.08 (s, 1H), 11.02 (s, 1H), 9.04 (d, aminooctyl)- J =3.2 Hz, 2H), 8.56 (t, J = 5.6 Hz, carbamate 1H), 8.26 (d, J = 5.2 Hz,1H), 8.13 (s, (CAS# 88829- 1H), 8.11-8.07 (m, 2H), 8.06-7.99 82-7) (m,2H), 7.77 (s, 1H), 7.70 (t, J = 6.4 Hz, 1H), 7.62-7.54 (m, 1H), 7.27 (s,1H), 7.18 (dd, J = 1.2, 5.2 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.02 (d,J = 7.2 Hz, 1H), 6.52 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 5.2, 12.8 Hz,1H), 4.31- 4.20 (m, 2H), 3.31-3.25 (m, 4H), 2.94-2.83 (m, 1H), 2.63-2.58(m, 1H), 2.56-2.53 (m, 1H), 2.08-1.98 (m, 1H), 1.61-1.52 (m, 4H), 1.33(s, 8H) 133^(d) I-133 undecane-1,11- CN 940.0 11.09 (br s, 1H), 11.01(s, 1H), 9.06- diamine (CAS# 8.99 (m, 2H), 8.56 (t, J = 5.6 Hz, 1H),822-08-2) 8.26 (d, J = 5.6 Hz, 1H), 8.13 (s, 1H), 8.11-8.06 (m, 2H),8.01 (d, J = 8.8 Hz, 2H), 7.77 (s, 1H), 7.69 (t, J = 6.4 Hz, 1H),7.61-7.53 (m, 1H), 7.27 (s, 1H), 7.21-7.16 (m, 1H), 7.08 (d, J = 8.4 Hz,1H), 7.01 (d, J = 7.2 Hz, 1H), 6.50 (t, J = 5.6 Hz, 1H), 5.04 (dd, J =5.6, 12.8 Hz, 1H), 4.30-4.20 (m, 2H), 3.30-3.14 (m, 2H), 2.94-2.80 (m,1H), 2.63-2.54 (m, 2H), 2.09-1.97 (m, 1H), 1.55-1.50 (m, 4H), 1.35- 1.19(m, 16H) 134 I-134 tert-butyl N-[2-[2-(2- DE 926.9 1H NMR (400MHZ,DMSO-d6) 8 aminoethoxy)- 11.09 (s, 1H), 9.98 (s, 1H), 8.99 (d,ethoxy]-ethyl]- J = 4.8 Hz, 2H), 8.63 (s, 1H), 8.24 (d, carbamate J =4.8 Hz, 1H), 8.10-7.92 (m, 4H), (CAS# 153086-78-3) 7.68-7.49 (m, 2H),7.25 (s, 1H), 7.21 (d, J = 4.0 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 7.01(d, J = 6.4 Hz, 1H), 6.58 (s, 1H), 5.05 (d, J = 7.2 Hz, 1H), 4.34-4.15(m, 2H), 3.65-3.44 (m, 12H), 2.92-2.82 (m, 1H), 2.61-2.59 (m, 1H),2.57-2.54 (m, 1H), 2.10-1.95 (m, 1H) 135 I-135 tert-butyl N-[2-[2-(2- DD902.7 11.07 (s, 1H), 11.02 (s, 1H), 9.03 (s, aminoethoxy)- 1H), 9.00 (s,1H), 8.74 (s, 1H), 8.35 ethoxy]ethyl]- (s, 1H), 8.26 (d, J = 5.2 Hz,1H), 8.12 carbamate (d, J = 8.0 Hz, 1H), 8.07 (s, 1H), 7.85 (CAS#153086-78-3) (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.70- 7.60 (m, 2H),7.55-7.50 (m, 1H), 7.27 (s, 1H), 7.18 (d, J = 4.4 Hz, 1H), 7.06 (d, J =8.8 Hz, 1H), 7.00 (d, J = 6.8 Hz, 1H), 6.56 (s, 1H), 5.07- 4.98 (m, 1H),4.31-4.19 (m, 2H), 3.66-3.52 (m, 12H), 2.88-2.80 (m, 1H), 2.63-2.57 (m,1H), 2.57-2.55 (m, 1H), 2.03-1.99 (m, 1H) 136 I-136 tert-butyl(14-amino- DD 990.3 11.08 (s, 1H), 11.03 (s, 1H), 9.05 (s,3,6,9,12-tetraoxa- 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.37tetradecyl)-carbamate (s, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.14 (CAS#811442-84-9) (d, J = 7.2 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J = 7.2 Hz,1H), 7.75 (s, 1H), 7.70-7.61 (m, 2H), 7.58-7.52 (m, 1H), 7.27 (s, 1H),7.18 (d, J = 4.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 6.8 Hz,1H), 6.57 (s, 1H), 5.07- 5.01 (m, 1H), 4.28-4.21 (m, 2H), 3.55-3.43 (m,20H), 2.94-2.80 (m, 1H), 2.62-2.59 (m, 1H), 2.59-2.57 (m, 1H), 2.02-1.97(m, 1H) 137 I-137 tert-butyl N-[2-[2-(2- CU 912.4 12.09 (s, 1H), 11.08(s, 1H), 9.12 (s, aminoethoxy)- 1H), 8.63-8.60 (m, 1H), 8.28-8.21ethoxy]ethyl]- (m, 4H), 8.14 (s, 1H), 8.13-8.09 (m, carbamate 2H), 8.03(d, J = 8.8 Hz, 2H), 7.88 (s, (CAS# 153086-78-3) 1H), 7.65 (d, J = 5.6Hz, 1H), 7.60- 7.53 (m, 1H), 7.50 (s, 1H), 7.19 (t, J = 6.8 Hz, 1H),7.12 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 5.6 Hz,1H), 5.06 (dd, J = 5.2, 13.2 Hz, 1H), 4.41-4.22 (m, 2H), 3.65-3.60 (m,2H), 3.61-3.56 (m, 6H), 3.45 (d, J = 5.6 Hz, 4H), 2.93-2.82 (m, 1H),2.63-2.55 (m, 1H), 2.55- 2.53 (m, 1H), 2.08-1.99 (m, 1H) 138^(e) I-138tert-butyl N-[2-[2-(2- DF 874.4 10.84 (s, 1H), 10.77 (s, 1H), 8.79 (s,aminoethoxy)- 1H), 8.77 (s, 1H), 8.40-8.36 (m, ethoxy]ethyl]- 1H), 7.93(d, J = 5.6 Hz, 1H), 7.90- carbamate 7.82 (m, 3H), 7.80-7.76 (m, 2H),(CAS# 153086-78-3) 7.53 (s, 1H), 7.35-7.30 (m, 1H), 6.94- 6.86 (m, 3H),6.80-6.75 (m, 2H), 6.35 (t, J = 6.0 Hz, 1H), 4.81 (dd, J = 5.6, 13.2 Hz,1H), 3.42-3.30 (m, 8H), 3.23-3.19 (m, 2H), 2.99-2.92 (m, 2H), 2.69-2.58(m, 1H), 2.37-2.28 (m, 4H), 1.83-1.75 (m, 1H), 0.87- 0.77 (m, 1H),0.26-0.18 (m, 2H), 0.02-0.04 (m, 2H) 139 I-139 tert-butyl N-[2-[2-(2- CW908.4 11.09 (s, 1H), 10.94 (d, J = 3.6 Hz, aminoethoxy)- 1H), 8.96 (d, J= 6.4 Hz, 1H), 8.34 (d, ethoxy]ethyl]- J = 16.8 Hz, 1H), 8.25 (d, J =5.2 Hz, carbamate 1H), 7.87-7.74 (m, 1H), 7.72-7.61 (CAS# 153086-78-3)(m, 2H), 7.61-7.55 (m, 1H), 7.51 (s, 1H), 7.26 (s, 1H), 7.19-7.10 (m,2H), 7.04 (t, J = 7.2 Hz, 1H), 6.65-6.56 (m, 1H), 5.06-5.04 (m, 1H),4.35- 4.27 (m, 1H), 4.26-4.19 (m, 2H), 3.66-3.53 (m, 6H), 3.51-3.44 (m,4H), 3.30-3.14 (m, 2H), 2.94-2.83 (m, 1H), 2.64-2.57 (m, 1H), 2.56- 2.53(m, 1H), 2.46-2.37 (s, 1H), 2.24- 2.17 (m, 1H), 2.13-2.02 (m, 2H),1.94-1.76 (m, 4H), 1.66-1.53 (m, 2H) 140^(h) I-140 tert-butylN-[2-[2-(2- EE 805.4 11.18-11.06 (m, 2H), 9.10 (s, 1H), aminoethoxy)-9.03 (s, 1H), 8.85 (d, J = 6.0 Hz, 2H), ethoxy]ethyl]- 8.62 (t, J = 5.4Hz, 1H), 8.15 (s, 1H), carbamate 8.11-8.06 (m, 2H), 8.05-8.00 (m, (CAS#153086-78-3) 2H), 7.97 (d, J = 6.0 Hz, 2H), 7.82 (s, 1H), 7.60-7.52 (m,1H), 7.12 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.59 (t, J =6.0 Hz, 1H), 5.05 (dd, J = 5.4, 12.8 Hz, 1H), 3.65-3.53 (m, 8H),3.43-3.41 (m, 4H), 2.94-2.82 (m, 1H), 2.63-2.57 (m, 1H), 2.58-2.56 (m,1H), 2.03-1.99 (m, 1H) 141 I-141 EF CN 886.3 11.08 (s, 1H), 11.02 (s,1H), 9.03 (s, 2H), 8.57 (t, J = 4.8 Hz, 1H), 8.25 (d, J = 5.6 Hz, 1H),8.13 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 8.02 (d, J = 8.8 Hz, 2H), 7.77(s, 1H), 7.70 (t, J = 6.4 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.27 (s,1H), 7.18 (d, J = 5.2 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (d, J =6.8 Hz, 1H), 6.67 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 5.6, 13.2 Hz, 1H),4.32-4.18 (m, 2H), 3.50-3.44 (m, 4H), 3.41-3.37 (m, 4H), 2.94-2.80 (m,1H), 2.59- 2.53 (m, 2H), 2.06-1.97 (m, 1H), 1.87-1.78 (m, 4H) 142 I-142tert-butyl N-[2-[2-(2- EC 854.1 9.12 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H),aminoethoxy)- 8.48 (d, J = 7.2 Hz, 1H), 8.37 (s, 1H), ethoxy]ethyl]-8.05-7.98 (m, 4H), 7.83 (d, J = 5.6 carbamate Hz, 1H), 7.67-7.35 (m,2H), 7.11 (d, (CAS# 153086-78-3) J = 8.4 Hz, 1H), 7.01 (d, J = 7.2 Hz,1H), 6.59 (t, J = 5.6 Hz, 1H), 6.45 (d, J = 7.2 Hz, 1H), 6.31 (s, 1H),5.08- 5.01 (m, 1H), 4.33-4.24 (m, 1H), 3.65-3.62 (m, 2H), 3.57-3.54 (m,11H), 2.92-2.81 (m, 1H), 2.62-2.55 (m, 1H), 2.54-2.52 (m, 1H), 2.07-1.97 (m, 1H), 1.83-1.73 (m, 2H), 1.70-1.53 (m, 4H), 1.46-1.30 (m, 2H)143 I-143 tert-butyl N-[2-[2-(2- DZ 903.0 11.09 (s, 1H), 11.03 (s, 1H),9.24 (d, aminoethoxy)- J = 2.4 Hz, 1H), 9.14 (s, 1H), 9.05 (s,ethoxy]ethyl]- 1H), 8.71 (t, J = 5.6 Hz, 1H), 8.56 carbamate (dd, J =2.8, 8.4 Hz, 1H), 8.26 (d, J = (CAS# 153086-78-3) 5.6 Hz, 1H), 8.20 (s,1H), 8.16 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.71 (t, J = 6.4 Hz, 1H),7.54 (t, J = 7.6Hz, 1H), 7.27 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H), 7.11(d, J = 8.8 Hz, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.58 (t, J = 5.6 Hz, 1H),5.04 (dd, J = 5.2, 12.8 Hz, 1H), 4.28- 4.22 (m, 2H), 3.64 (d, J = 5.6Hz, 2H), 3.61-3.58 (m, 6H), 3.51-3.46 (m, 4H), 2.92-2.82 (m, 1H),2.61-2.59 (m, 1H), 2.57-2.55 (m, 1H), 2.03-2.01 (m, 1H) Variations inreaction time for Method 11 were as follows: Step 1 was run anywherefrom 12-16 h, Step 2 anywhere from 10 min-12 h, Step 3 anywhere from0.5-12 h, and Step 4 was run anywhere from 20 min-10 h. The product ofStep 3 was also extracted with EtOAc when it did not precipitate out ofsolution. ªThe product of Step 1 was purified by prep-TLC (SiO₂, PE:EA =1:2). ^(b)The product of Step 3 was purified by prep-HPLC (column:Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B%: 55%-85%). ^(c)The final product was purified by prep-HPLCunder basic conditions (column: Phenomenex Luna Phenyl-Hexyl 150_30_5um; mobile phase: [water (10 mM NH₄HCO₃)-ACN]; B%: 45%-90%). ^(d)Step 2,the first deprotection step with HCl was skipped as there was no BOCgroup to deprotect from the amine intermediate. ^(e)Step 4 was run in amixed solvent of DCM (1 mL) and DMF (2 mL). ^(f)The deprotection of theCBZ group in Step 2 was achieved with a hydrogenation using Pd(OH)₂/Cand hydrogen gas (15 psi pressure) in THF at rt for 16 h. ^(g)Thedeprotection of the benzyl groups in Step 2 was achieved with ahydrogenation using Pd(OH)₂/C, Pd/C and hydrogen gas (15 psi pressure)in THF and a catalytic amount of HCl at rt for 20 h. After filtrationand concentration, the intermediate was purified by reversed phasechromatography (0.1% NH₃ H₂O). The final product was also purified byreversed phase chromatography using TFA not FA as the acidic modifier.^(h)Step 4 was skipped as no deprotection was required.

Further Examples Using Synthetic Methods Similar to Method 11 Example144:N-[3-carbamoyl-1-[4-[2-[5-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]pentylamino]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-144

4-(5-aminopentylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dionewas synthesized via Steps 1-2 of Method 11, where fluoride IntermediateR was coupled with amine tert-butyl N-(5-aminopentyl)carbamate (CAS#51644-96-3) in the first step, and Step 2 was run at rt for 1 hr. Step3 involved a reductive amination performed as follows: to a solution of4-(5-aminopentylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(300 mg, 759 umol, HCl) and tert-butyl N-(2-oxoethyl)carbamate (193 mg,1.22 mmol, CAS #89711-08-0) in THF (60 mL) was added KOAc (149 mg, 1.52mmol) and NaBH(OAc)₃ (402 mg, 1.90 mmol). The mixture was stirred at rtfor 20 hours. On completion, the reaction mixture was added to ice water(100 mL) and extracted with DCM (3×60 mL). The organic phase wascollected, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-HPLC (0.1% FA) to givetert-butylN-[2-[5-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]pentylamino]ethyl]carbamate (180 mg, 42% yield) as a yellow solid gum (LC-MS (ESI⁺)m/z 502.2 (M+H)⁺).

Step 4 followed Method 11 with deprotection of the Boc group with HCl indioxane. This intermediate was carried on without purification to thefinal step which was performed as follows: to a mixture of4-[5-(2-aminoethylamino)pentylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(110 mg, 251 umol, HCl salt) and DIPEA (162 mg, 1.26 mmol) in DMF (3 mL)was added4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (123 mg, 200 umol, Intermediate CN) and HATU (114 mg, 301 umol).The reaction mixture was stirred at rt for 0.5 hour. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byreverse phase (0.1% HCl), then it was purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]) to give the title compound I-144 (11.4 mg, 4% yield, FA) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.05 (d, J=2.4Hz, 2H), 8.70 (s, 1H), 8.33 (s, 1H), 8.27 (d, J=5.6 Hz, 1H), 8.14 (s,1H), 8.13-8.00 (m, 4H), 7.78 (s, 1H), 7.71 (t, J=6.4 Hz, 1H), 7.61-7.55(m, 1H), 7.28 (s, 1H), 7.20-7.16 (m, 1H), 7.10 (d, J=8.4 Hz, 1H),7.04-6.99 (m, 1H), 6.54 (t, J=5.8 Hz, 1H), 5.06 (dd, J=5.5, 13.2 Hz,1H), 4.32-4.21 (m, 2H), 3.40-3.27 (m, 4H), 2.95-2.84 (m, 3H), 2.81 (t,J=6.0 Hz, 2H), 2.66-2.61 (m, 3H), 2.06-2.00 (m, 1H), 1.64-1.47 (m, 4H),1.44-1.35 (m, 2H); LC-MS (ESI⁺) m/z 899.4 (M+H)⁺.

Example 145:N-[3-carbamoyl-1-[1-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]-4-piperidyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-145

To a solution of triphosgene (14.4 mg, 48.5 umol) in DCM (2 mL) wasadded a solution of4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(42.8 mg, 97.1 umol, HCl salt, synthesized via Steps 1-2 of Example 127)in DCM (3 mL) at 0° C. Then TEA (49.1 mg, 485 umol) was added to thesolution dropwise at 0° C., followed byN-[3-carbamoyl-1-(4-piperidyl)pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide (50.0 mg, 97.1 umol,HCl salt, Intermediate CX). The reaction mixture was then stirred at 0°C. for 1 hour. On completion, the reaction mixture was concentrated invacuo. The residue was purified by prep-HPLC (column: Boston Green ODS150*30 5u; mobile phase: [water (0.225% FA)-ACN]) to give the titlecompound I-145 (20.4 mg, 22% yield, FA) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.10 (s, 1H), 10.95 (s, 1H), 8.98 (s, 1H), 8.39 (s,1H), 8.25 (d, J 5.2 Hz, 1H), 7.75-7.67 (m, 2H), 7.62-7.55 (m, 1H), 7.52(s, 1H), 7.26 (s, 1H), 7.17 (d, J=1.2 Hz, 1H), 7.16-7.13 (m, 1H),7.12-7.12 (m, 1H), 7.04 (d, J 7.2 Hz, 1H), 6.62-6.60 (m, 2H), 5.07 (dd,J 5.6, 12.8 Hz, 1H), 4.50-4.41 (m, 1H), 4.30-4.19 (m, 2H), 4.09 (d, J12.8 Hz, 2H), 3.65-3.61 (m, 2H), 3.59-3.52 (m, 4H), 3.48-3.45 (m, 2H),3.44-3.41 (m, 2H), 3.24-3.13 (m, 2H), 2.95-2.86 (m, 1H), 2.86-2.78 (m,2H), 2.62-2.57 (m, 1H), 2.56 m 2.53 (m, 1H), 2.05-1.96 (m, 3H),1.89-1.78 (m, 2H); LC-MS (ESI⁺) m/z 909.1 (M+H)⁺.

Example 146 (Method 12):N-(3-carbamoyl-1-(4-((2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propoxy)ethyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide,I-146

Step 1—Tert-Butyl(4-(4-((3-carbamoyl-1-(4-((2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propoxy)ethyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate

To a solution of4-[3-(2-aminoethoxy)propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(90 mg, 250 umol, Intermediate CP) and (154 mg, 250 umol, IntermediateCN) in DMF (2 mL) was added DIPEA (162 mg, 1.25 mmol). Ten minuteslater, HATU (114 mg, 300 umol) was added into the above mixture. Thereaction mixture was stirred at rt for 0.5 h. On completion, the mixturewas diluted was water (30 mL), stirred and filtered. The filter cake wasdried in vacuo to give the title compound (110 mg, 43% yield) as a whitesolid. LC-MS (ESI⁺) m/z 957.3 (M+H)⁺.

Step2—N-(3-carbamoyl-1-(4-((2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)propoxy)ethyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]propoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(110 mg, 115 umol) in DCM (2 mL) was added HCl in dioxane (4 M, 2 mL).The reaction mixture was stirred at rt for 17 h. On completion, themixture was concentrated in vacuo. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 32%-62%) to give the title compound I-146 (13.3mg, 13%˜yield, FA) as a white solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.11(s, 1H), 11.02 (s, 1H), 9.04 (d, J 5.2 Hz, 2H), 8.71-8.62 (m, 1H), 8.26(d, J=5.2 Hz, 1H), 8.15-8.07 (m, 3H), 8.07-8.02 (m, 2H), 7.84-7.75 (m,3H), 7.73-7.67 (m, 2H), 7.28 (s, 1H), 7.19 (d, J=5.2 Hz, 1H), 5.14 (dd,J=5.2, 13.2 Hz, 1H), 4.32-4.19 (m, 2H), 3.54 (t, J=5.2 Hz, 2H),3.48-3.43 (m, 4H), 2.96-2.87 (m, 1H), 2.86-2.83 (m, 2H), 2.63-2.59 (m,2H), 2.11-2.02 (m, 1H), 1.93-1.84 (m, 2H); LC-MS (ESI⁺) m/z 857.3 (M+H)

TABLE 10 Compounds synthesized via Method 12 with the coupling ofvarious amines and acids in Step 1. LCMS Step 1 Step 1 (ES+)Intermediate Intermediate m/z Ex-# I-# Amine Acid (M + H)⁺ ¹HNMR (400MHz, DMSO-d6) δ 147 I-147 CQ CN 901.3 11.10 (s, 1H), 11.01 (s, 1H), 9.02(d, J = 5.6 Hz, 2H), 8.64 (t, J = 5.6 Hz, 1H), 8.26 (d, J = 5.2 Hz, 1H),8.14- 8.06 (m, 3H), 8.05-7.99 (m, 2H), 7.82-7.73 (m, 3H), 7.72-7.66 (m,2H), 7.28 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 5.12 (dd, J = 5.2, 12.8 Hz,1H), 4.30-4.21 (m, 2H), 3.60-3.45 (m, 10H), 2.81-2.76 (m, 1H), 2.79 (t,J = 7.2 Hz, 2H), 2.63-2.60 (m, 1H), 2.63-2.60 (m, 1H), 2.58-2.56 (m,1H), 2.09-2.03 (m, 1H), 1.87-1.80 (m, 1H) 148 I-148 CT CN 989.9 11.12(s, 1H), 11.01 (s, 1H), 9.04 (d, J = 2.4 Hz, 2H), 8.64 (t, J = 5.2 Hz,1H), 8.26 (d, J = 5.2 Hz, 1H), 8.18- 8.07 (m, 3H), 8.07-8.00 (m, 2H),7.84-7.74 (m, 3H), 7.74-7.67 (m, 2H), 7.27 (s, 1H), 7.18 (d, J = 5.2 Hz,1H), 5.13 (dd, J = 5.2, 12.8 Hz, 1H), 4.33-4.20 (m, 2H), 3.59-3.37 (m,18H), 2.95-2.76 (m, 3H), 2.65- 2.57 (m, 2H), 2.11-1.99 (m, 1H),1.90-1.82 (m, 2H) 149 I-149 CS CN 985.9 11.12 (s, 1H), 11.01 (s, 1H),9.04 (s, 2H), 8.65 (t, J = 5.2 Hz, 1H), 8.26 (d, J = 5.2 Hz, 1H),8.16-8.08 (m, 3H), 8.07-8.00 (m, 2H), 7.95-7.89 (m, 3H), 7.77 (s, 1H),7.71 (t, J = 6.4 Hz, 1H), 7.27 (s, 1H), 7.18 (dd, J = 1.6, 5.2 Hz, 1H),5.16 (dd, J = 5.2, 12.8 Hz, 1H), 4.46 (s, 2H), 4.31-4.19 (m, 2H),3.68-3.62 (m, 2H), 3.61-3.50 (m, 12H), 3.49-3.41 (m, 2H), 2.95- 2.82 (m,1H), 2.64-2.54 (m, 2H), 2.11-2.02 (m, 1H) 150 I-150 EL EG 896.0 10.87(s, 1H), 9.74 (s, 1H), 8.77 (s, 1H), 8.75 (s, 1H), 8.34 (t, J = 5.2 Hz,1H), 8.07 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.83-7.72 (m, 4H),7.38-7.32 (m, 1H), 6.91-6.77 (m, 5H), 6.56 (t, J = 4.8 Hz, 1H), 4.82(dd, J = 5.6, 12.8 Hz, 1H), 3.06-3.03 (m, 2H), 2.97-2.94 (m, 1H),2.72-2.53 (m, 4H), 2.40-2.30 (m, 4H), 2.29-2.28 (m, 2H), 1.83-1.75 (m,1H), 1.36- 1.22 (m, 4H), 1.18-1.11 (m, 2H), 0.88-0.80 (m, 1H), 0.26-0.20(m, 2H), 0.02-−0.03 (m, 2H) 151 I-151 EJ CN 957.3 11.10 (s, 1H), 11.02(s, 1H), 9.04 (s, 2H), 8.66-8.64 (m, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.15(s, 1H), 8.12- 8.06 (m, 3H), 7.78 (s, 1H), 7.71 (t, J = 6.8 Hz, 1H),7.61-7.54 (m, 1H), 7.27 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.14 (d, J =8.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.60 (s, 1H), 5.06 (dd, J = 12.0,5.2 Hz, 1H), 4.33-4.17 (m, 4H), 3.76-3.70 (m, 12H), 2.97- 2.90 (m, 1H),2.34-2.30 (m, 2H), 2.12-1.95 (m, 4H) Variations in reaction time forMethod 12 were as follows: Step 1 was run anywhere from 0.5-12 h, andStep 2 anywhere from 10 min-17 h. If the product of Step 1 was not aprecipitate, a standard work up with water and extraction with ethylacetate was used to isolate the product.

Example 152 (Method 13):N-[3-carbamoyl-1-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetyl]-4-piperidyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide.I-152

Step 1—Tert-Butyl2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)acetate

To a solution of tert-butyl 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetate(6.40 g, 24.3 mmol, Intermediate CY) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (6.71 g, 24.3mmol, Intermediate R) in dioxane (100 mL) was added DIPEA (9.42 g, 72.9mmol). The reaction mixture was stirred at 115° C. for 24 hours. Oncompletion, the reaction mixture was concentrated in vacuo to giveyellow oil. The yellow oil was purified by prep-HPLC (water (0.1%FA)-ACN) to give the title compound (6.00 g, 48% yield) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.54-7.45 (m, 1H), 7.11 (d,J=8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.52-6.48 (m, 1H), 4.99-4.87 (m,1H), 4.02 (s, 2H), 3.75-3.68 (m, 10H), 3.50-3.46 (m, 2H), 2.93-2.69 (m,3H), 2.17-2.10 (m, 1H), 1.49 (s, 9H).

Step2—2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)acetic Acid

To a solution of tert-butyl2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetate (6.00 g, 11.6 mmol) in DCM (30 mL) wasadded TFA (30.8 g, 270 mmol). The reaction mixture was stirred at rt for12 hours. On completion, the reaction mixture was concentrated in vacuoto give the title compound (5.60 g, 99% yield) as a yellow oil. LC-MS(ESI⁺) m/z 464.0 (M+H)⁺.

Step3—N-[3-carbamoyl-1-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetyl]-4-piperidyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture ofN-[3-carbamoyl-1-(4-piperidyl)pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(50.0 mg, 97.1 umol, Intermediate CX) and DIPEA (125 mg, 971 umol) inDMF (5 mL) was added2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetic acid (54.0 mg, 116 umol) and HATU (44.3 mg, 116 umol). Thereaction mixture was stirred at rt for 0.5 hour. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]) to give the title compound I-152 (55.7 mg, 59%yield, FA) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H),10.94 (s, 1H), 8.96 (s, 1H), 8.39 (s, 1H), 8.25 (d, J=5.6 Hz, 1H),7.74-7.66 (m, 2H), 7.62-7.54 (m, 1H), 7.51 (s, 1H), 7.26 (s, 1H), 7.16(d, J=5.2 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 7.03 (d, J=7.2 Hz, 1H), 6.59(s, 1H), 5.05 (dd, J=5.6, 12.8 Hz, 1H), 4.61-4.39 (m, 2H), 4.32-4.21 (m,2H), 4.20-4.12 (m, 2H), 3.94 (d, J=13.6 Hz, 1H), 3.63-3.59 (m, 2H),3.58-3.53 (s, 8H), 3.46 (d, J=5.2 Hz, 2H), 3.18-3.10 (m, 1H), 2.94-2.83(m, 1H), 2.83-2.71 (m, 1H), 2.63-2.56 (m, 1H), 2.56-2.53 (m, 1H),2.07-1.92 (m, 4H), 1.85 (d, J=9.6 Hz, 1H); LC-MS (ESI⁺) m/z 924.3 (M+H).

TABLE 11 Compounds synthesized via Method 13 with the addition ofvarious amines to fluoride Intermediate R in Step 1, followed bycoupling with various amines in Step 3. LCMS Step 1 Step 3 (ES+)Intermediate Intermediate m/z Ex-# I-# Amine Amine (M + H)⁺ 1HNMR (400MHz, DMSO-d6) δ 153 I-153 DS DR 803.3 11.11 (br s, 1H), 8.53 (s, 1H),7.65- 7.55 (m, 1H), 7.21-7.13 (m, 2H), 7.11 (s, 1H), 7.06 (d, J = 6.8Hz, 1H), 6.68 (t, J = 5.6 Hz, 1H), 5.20-5.11 (m, 1H), 5.07 (dd, J = 5.6,12.8 Hz, 1H), 4.20 (s, 2H), 3.93 (t, J = 6.4 Hz, 1H), 3.71-3.60 (m, 2H),3.53-3.49 (m, 3H), 3.47-3.44 (m, 3H), 3.14- 2.99 (m, 2H), 2.96-2.88 (m,2H), 2.66-2.54 (m, 4H), 2.44-2.40 (m, 5H), 2.32-2.25 (m, 1H), 2.18-2.02(m, 3H), 1.81-1.79 (m, 2H), 1.69- 1.48 (m, 3H), 1.42-1.27 (m, 2H) 154ªI-154 CZ CX 880.4 11.11 (s, 1H), 10.93 (s, 1H), 8.97 (s, 1H), 8.39 (s,1H), 8.25 (d, J = 5.6 Hz, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.57 (t, J =7.6 Hz, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 7.19-7.11 (m, 2H), 7.03 (d, J =7.2 Hz, 1H), 6.60 (s, 1H), 5.06 (dd, J = 5.2, 13.2 Hz, 1H), 4.58-4.41(m, 2H), 4.30-4.22 (m, 2H), 4.20 (s, 2H), 3.92 (d, J = 12.8 Hz, 1H),3.70- 3.53 (m, 8H), 3.47 (d, J = 4.8 Hz, 4H), 3.25-3.04 (m, 1H),2.91-2.80 (m, 1H), 2.77-2.71 (m, 1H), 2.61 (s, 1H), 2.58-2.56 (m, 1H),2.04 (s, 4H), 1.85 (d, J = 9.2 Hz, 1H) 155 I-155 DA CX 968.5 11.10 (s,1H), 10.94 (s, 1H), 8.97 (s, 1H), 8.40 (s, 1H), 8.24 (d, J = 5.2 Hz,1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.60- 7.55 (m, 1H), 7.52 (s, 1H), 7.25(s, 1H), 7.17-7.14 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 6.8Hz, 1H), 6.62-6.55 (m, 1H), 5.05 (dd, J = 5.6, 13.2 Hz, 1H), 4.63-4.39(m, 2H), 4.24 (dd, J = 6.4, 9.6 Hz, 2H), 4.18 (d, J = 6.8 Hz, 2H), 3.94(d, J = 13.2 Hz, 1H), 3.60 (d, J = 5.2 Hz, 2H), 3.57-3.49 (m, 12H),3.48-3.44 (m, 2H), 3.21-3.07 (m, 1H), 2.93-2.85 (m, 1H), 2.80-2.73 (m,1H), 2.64- 2.59 (m, 1H), 2.58-2.56 (m, 1H), 2.08-1.91 (m, 4H), 1.86 (d,J = 14.4 Hz, 1H 156ª I-156 CZ DB 852.4 11.10 (s, 1H), 10.91 (s, 1H),8.97 (s, 1H), 8.48 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.84 ( s, 1H),7.69 (t, J = 6.4 Hz, 1H), 7.58 (s, 1H), 7.57-7.51 (m, 1H), 7.25 (s, 1H),7.17 (d, J = 5.2 Hz, 1H), 7.10 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 6.8 Hz,1H), 6.55 (s, 1H), 5.45-5.34 (m, 1H), 5.08-5.01 (m, 1H), 4.70- 4.63 (m,1H), 4.60-4.53 (m, 1H), 4.41-4.33 (m, 1H), 4.29-4.20 (m, 3H), 4.11-4.03(m, 2H), 3.63-3.46 (m, 8H), 2.91-2.82 (m, 1H), 2.64- 2.57 (m, 1H),2.57-2.55 (m, 1H), 2.06-2.00 (m, 1H) 157 I-157 DA DB 940.5 11.10 (s,1H), 10.95 (s, 1H), 8.97 (s, 1H), 8.52 (s, 1H), 8.24 (d, J = 5.2 Hz,1H), 7.88 (s, 1H), 7.68 (t, J = 6.8 Hz, 1H), 7.59 (s, 1H), 7.55 (d, J =8.4 Hz, 1H), 7.24 (s, 1H), 7.15 (d, J = 4.4 Hz, 1H), 7.11 (d, J = 8.8Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H), 6.60-6.55 (m, 1H), 5.47-5.37 (m, 1H),5.08-5.01 (m, 1H), 4.72-4.62 (m, 1H), 4.58-4.50 (m, 1H), 4.41-4.32 (m,1H), 4.30- 4.19 (m, 3H), 4.04 (s, 2H), 3.61-3.49 (m, 16H), 2.93-2.87 (m,1H), 2.63- 2.60 (m, 1H), 2.58-2.57 (m, 1H), 2.06-2.00 (m, 1H) 158 I-158CY DB 896.4 11.11 (s, 1H), 10.94 (s, 1H), 8.97 (s, 1H), 8.51 (s, 1H),8.24 (d, J = 5.2 Hz, 1H), 7.89 (s, 1H), 7.74-7.65 (m, 1H), 7.60 (s, 1H),7.57-7.50 (m, 1H), 7.24 (s, 1H), 7.16 (d, J = 4.8 Hz, 1H), 7.09 (d, J =8.4 Hz, 1H), 7.01 (d, J = 6.8 Hz, 1H), 6.61-6.52 (m, 1H), 5.48- 5.35 (m,1H), 5.08-5.02 (m, 1H), 4.73-4.62 (m, 1H), 4.59-4.49 (m, 1H), 4.40-4.33(m, 1H), 4.30-4.21 (m, 3H), 4.03 (s, 2H), 3.61-3.58 (m, 2H), 3.57-3.53(m, 10H), 2.91-2.85 (m, 1H), 2.63-2.59 (m, 1H), 2.57- 2.55 (m, 1H),2.05-1.97 (m, 1H) Variations in reaction time for Method 13 were asfollows: Step 1 was run anywhere from 16-24 h and Step 2 was runanywhere from 0.5-16 h. ªSince the product of Step 1 was the ethylester, not BOC ester, the deprotection for Step 2 used (Bu₃Sn)₂O intoluene and the reaction mixture was stirred at 115 ° C. for 4 hours.This intermediate was then purified by prep-HPLC (0.1% FA.)

Further Examples Using Synthetic Methods Similar to Method 13 Example159:N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl-methyl-carbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-159

Step1—2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethanamine(350 mg, 1.24 mmol, Intermediate CR) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (342 mg, 1.24mmol, Intermediate R) in dioxane (5 mL) was added DIPEA (1.60 g, 12.3mmol, 2.16 mL). The reaction mixture was stirred at 115° C. for 16hours. On completion, the mixture was concentrated in vacuo to give aresidue. The residue was purified by reverse phase (0.1% NH₃ H₂O) togive the title compound (600 mg, 89% yield) as a yellow oil. LC-MS(ESI⁺) m/z 539.4 (M+H)⁺.

Step2—2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a mixture of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-[(4-methoxyphenyl)methyl-methyl-amino]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione (0.10 g, 185 umol) in MeOH (3mL) and 1N HCl (0.05 mL) was added Pd/C (0.05 g, 10 wt %) and Pd(OH)₂/C(0.05 g, 10 wt %). Then the reaction mixture was stirred at rt for 2hours under hydrogen atmosphere (15 psi pressure). On completion, themixture was filtered and the filtrate was concentrated in vacuo to givethe title compound (60.0 mg, 77% yield) as a yellowish oil. LC-MS (ESI⁺)m/z 419.1 (M+H)⁺.

Step 3—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl-methyl-carbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a mixture of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione(77.0 mg, 169 umol, HCl) and4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (88.5 mg, 143 umol, Intermediate CN) in DMF (3 mL) was added DIPEA(109 mg, 846 umol, 147 uL). Then HATU (83.6 mg, 220 umol) was added tothe mixture. The reaction mixture was stirred at rt for 12 hours. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 50%-80%) togive the title compound (0.05 g, 23% yield) as white solid. LC-MS (ESI⁺)m/z 1016.0 (M+H)⁺.

Step4—N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl-methyl-carbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl-methyl-carbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(42.0 mg, 41.3 umol) in DCM (3 mL) was added HCl in dioxane (4 M, 0.3mL). Then the reaction mixture was stirred at rt for 0.5 hour. Oncompletion, the mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column:Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 31%-61%) togive the title compound I-159 (20.0 mg, 50% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ11.15-10.96 (m, 2H), 9.18-8.78 (m, 2H), 8.27 (s,1H), 8.12-7.96 (m, 3H), 7.78-7.50 (m, 5H), 7.31-7.00 (m, 4H), 6.58 (s,1H), 5.05 (s, 1H), 4.25 (s, 2H), 3.70-3.62 (s, 8H), 3.55-3.49 (m, 4H),2.98 (s, 3H), 2.87 (s, 1H), 2.65-2.58 (m, 2H), 2.02-2.00 (m, 1H); LC-MS(ESI⁺) m/z 916.3 (M+H)⁺.

Example 160:(2S)-3-[(8R)-1-[4-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]acetyl]piperazin-1-yl]cyclohexoxy]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]-2-hydroxy-propanamide,I-160

The title compound was synthesized via Method 13, using fluorideIntermediate R and amine intermediate CZ in the first step which was runat 115° C. for 18 hours. In Step 2, the ester was deprotected asfollows: to a mixture of (Bu₃Sn)₂O (1.17 g, 1.97 mmol) in toluene (5 mL)was added ethyl 2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl] amino] ethoxy] ethoxy] acetate (440 mg, 983umol). The reaction mixture was stirred at 115° C. for 4 hours. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% FA) to give2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1, 3-dioxo-isoindolin-4-yl] amino]ethoxy] ethoxy] acetic acid (230 mg, 55% yield) as a yellow solid (LC-MS(ESI⁺) m/z 420.1 (M+H); ¹H NMR (400 MHz, DMSO-d₆) δ=13.39-11.73 (m, 1H),11.10 (s, 1H), 7.65-7.52 (m, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (d, J=7.2Hz, 1H), 7.08-7.02 (m, 1H), 6.62 (t, J=5.6 Hz, 1H), 5.06 (dd, J=5.2,12.8 Hz, 1H), 4.02 (s, 2H), 3.67-3.56 (m, 6H), 3.52-3.46 (m, 2H),2.95-2.81 (m, 1H), 2.69-2.54 (m, 2H), 2.07-1.99 (m, 1H)). IntermediateDR was used as the amine in Step 3 to give the final compound I-160.Characterization data: ¹H NMR (400 MHz, DMSO-d₆) δ=11.12 (s, 1H), 8.52(s, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.15 (dd, J=9.6, 18.4 Hz, 3H), 7.05 (d,J=6.8 Hz, 1H), 6.60 (s, 1H), 5.11 (d, J=11.2 Hz, 1H), 5.06 (dd, J=5.2,12.8 Hz, 1H), 4.14 (s, 2H), 3.95-3.90 (m, 5H), 3.64 (d, J=4.8 Hz, 2H),3.59-3.55 (m, 4H), 3.52-3.34 (m, 8H), 3.02 (dd, J=8.4, 16.0 Hz, 1H),2.94-2.86 (m, 2H), 2.65-2.54 (m, 3H), 2.41 (d, J=9.6 Hz, 2H), 2.33-2.26(m, 1H), 2.16-2.04 (m, 3H), 1.82 (d, J=10.0 Hz, 2H), 1.64-1.47 (m, 3H),1.43-1.31 (m, 2H). LC-MS (ESI⁺) m/z 847.1 (M+H)⁺.

Example 161:(2S)-3-[(8R)-1-[4-[4-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]piperazin-1-yl]cyclohexoxy]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]-2-hydroxy-propanamide,I-161

The title compound was synthesized via Method 13, using fluorideIntermediate R and amine Intermediate DW in the first step which was runat 115° C. for 16 hours. In Step 2, the ester was deprotected asfollows: to a solution of (Bu₃Sn)₂O (779 mg, 1.31 mmol) in toluene (20mL) was added ethyl2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetate(0.35 g, 654 umol). The reaction mixture was stirred at 115° C. for 12hours. On completion, the reaction mixture was quenched with 1 N sodiumfluoride solution. The mixture was extracted with DCM (100 mL), thendried and concentrated in vacuo. The crude was purified by reverse phaseflash chromatography (0.1% FA) to give2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (0.175 g, 53% yield) as yellow oil (LCMS(M+1)⁺: 508.2). Intermediate DR was used as the amine in Step 3 to givethe final compound I-161. Characterization data: ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.52 (s, 1H), 7.58 (t, J=7.6 Hz, 1H),7.21-7.07 (m, 3H), 7.04 (d, J=7.2 Hz, 1H), 6.61 (t, J=5.6 Hz, 1H),5.21-5.11 (m, 1H), 5.10-5.01 (m, 1H), 4.12 (s, 2H), 3.93 (t, J=6.4 Hz,1H), 3.66-3.62 (m, 2H), 3.60-3.49 (m, 20H), 3.07-3.00 (m, 1H), 2.94-2.84(m, 2H), 2.63-2.56 (m, 2H), 2.55-2.53 (m, 2H), 2.47-2.36 (m, 5H),2.32-2.26 (m, 1H), 2.20-2.08 (m, 2H), 2.06-1.99 (m, 1H), 1.90-1.79 (m,2H), 1.70-1.57 (m, 2H), 1.56-1.47 (m, 1H), 1.45-1.33 (m, 2H); LC-MS(ESI⁺) m/z 957.4 (M+Na)⁺.

Example 162 (Method 14):5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-[3-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidine-8-carboxamide,I-162

Step 1—Ethyl2-[2-[2-[2-[3-[(8-carbamoyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidin-7-yl)amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (819 mg, 2.61mmol, Intermediate BI) and7-(3-hydroxy-5-methoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(300 mg, 868 umol, Intermediate EZ) in DMF (10 mL) was added K₂CO₃ (360mg, 2.61 mmol). The mixture was stirred at 50° C. for 12 hours. Oncompletion, the reaction mixture was concentrated in vacuo to removesolvent. The residue was diluted with water (5 mL) and extracted withDCM (3×10 mL). The combined organic layer was dried over sodium sulfate,filtered and concentrated in vacuo to give the title compound (320 mg,65% yield) as a yellowish oil. LC-MS (ESI⁺) m/z 564.0 (M+H)⁺.

Step 2—Ethyl2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-aminocyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate

A solution of ethyl2-[2-[2-[2-[3-[(8-carbamoyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidin-7-yl)amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate(220 mg, 390 umol) and (1R,2S)-cyclohexane-1,2-diamine (89.1 mg, 781umol, CAS #1436-59-5) in DMF (2 mL) was stirred at 90° C. for 3 hours.On completion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was diluted with water (5 mL) and extracted withDCM (3×10 mL). The combined organic layer was dried over anhydroussodium sulfate, filtered and concentrated in vacuo to give the titlecompound (220 mg, 65% yield) as a yellowish oil. LC-MS (ESI⁺) m/z 630.1(M+H)

Step 3—Ethyl2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-aminocyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate(220 mg, 349 umol) and (Boc)₂O (152 mg, 699 umol) in MeOH (3 mL) wasadded 12 (17.7 mg, 69.9 umol). The reaction mixture was stirred rt for12 hours. On completion, the reaction mixture was concentrated in vacuoto remove solvent. The residue was diluted with water (5 mL) andextracted with DCM (3×5 mL). The combined organic layer was dried oversodium sulfate, filtered and concentrated in vacuo to give a residue.The residue was purified by silica gel column chromatography(DCM:MeOH=20:1) to give the title compound (150 mg, 58% yield) as ayellowish solid. LC-MS (ESI⁺) m/z 730.1 (M+H)⁺.

Step4—2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]aceticacid

To a solution of ethyl2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]acetate(150 mg, 205 umol) in a mixed solvent of THF (2 mL) and H₂O (2 mL) wasadded LiOH (19.7 mg, 822 umol). Then the mixture was stirred at rt for0.5 hour. On completion, saturated citric acid aqueous solution wasadded to the mixture to adjust the pH=5.0. The residue was diluted withwater (3 mL) and extracted with DCM (3×5 mL). The combined organic layerwas dried over sodium sulfate, filtered and concentrated in vacuo togive the title compound (135 mg, 94% yield) as white solid. LC-MS (ESI⁺)m/z 702.3 (M+H)⁺.

Step 5—Tert-ButylN-[(1R,2S)-2-[[8-carbamoyl-7-[3-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbamate

A solution of2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]aceticacid (135 mg, 192 umol) in DMF (2 mL) was cooled to 0° C. Then, DIPEA(67.8 mg, 525 umol),(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(75.3 mg, 175 umol, Intermediate CI) and HATU (79.8 mg, 210 umol) wereadded. Then the mixture allowed to warm to rt and stirred for 6 hours.On completion, the mixture was diluted with water (5 mL) and extractedwith EA (3×5 mL). The combined organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to give a residue. Theresidue was purified by reverse phase chromatography (0.1% FA in water)to give the title compound (90.0 mg, 46% yield) as a yellowish solid.LC-MS (ESI⁺) m/z 1114.2 (M+H)⁺.

Step6—5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-[3-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidine-8-carboxamide

To a solution oftert-butylN-[(1R,2S)-2-[[8-carbamoyl-7-[3-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbamate(90.0 mg, 80.8 umol) in MeOH (2 mL) was added HCl in dioxane (4 M, 2mL). Then the mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u;mobile phase: [water (0.225% FA)-ACN]) to give the title compound I-162(20.0 mg, 24% yield, FA salt) as white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 12.39 (s, 1H), 9.56 (d, J=3.2 Hz, 1H), 8.96 (s, 1H), 8.59 (t, J=5.6Hz, 1H), 8.14 (s, 1H), 7.48-7.36 (m, 6H), 7.32 (s, 1H), 6.92 (s, 1H),6.67 (s, 1H), 6.21 (s, 1H), 4.59-4.52 (d, J=9.6 Hz, 1H), 4.45-4.31 (m,4H), 4.29-4.18 (m, 2H), 4.12-4.00 (m, 3H), 3.96 (s, 2H), 3.74 (s, 4H),3.72-3.64 (m, 7H), 3.61-3.57 (m, 10H), 2.53-2.51 (m, 2H), 2.43 (s, 3H),2.10-1.98 (m, 2H), 1.92-1.80 (m, 2H), 1.76-1.70 (m, 2H), 1.47-1.34 (m,2H), 0.94 (s, 9H); LC-MS (ESI⁺) m/z 1014.2 (M+H)⁺.

TABLE 12 Compounds synthesized via Method 14 with the displacement ofvarious mesylates with alcohols in Step 1, followed by coupling ofvarious amines in Step 5. LCMS (ES+) Step 1 Step 1 Step 5 m/z ¹HNMR (400MHz, Ex-# I-# Mesylate Alcohol Amine (M + H)⁺ DMSO-d6) δ 163 I-163 ethyl2-[2-[2-[2-[2- EZ CI 1124.6ª 12.39 (s, 1H), 9.56 (s, 1H),(2-methylsulfonyl- 8.96 (s, 1H), 8.59 (t, J = 5.6 oxyethoxy)ethoxy]- Hz,1H), 8.14 (s, 1H), 7.48- ethoxy]ethoxy]- 7.34 (m, 6H), 7.31 (s, 1H),ethoxy]acetate 6.93 (s, 1H), 6.66 (s, 1H), 6.21 (synthesized (s, 1H),4.57-4.55 (d, J = 9.6 via Steps 1-2 of Hz, 1H), 4.48-4.31 (m, 3H),Intermediate BW) 4.29-4.19 (m, 2H), 4.06 (s, 3H), 3.95 (s, 2H),3.80-3.74 (m, 4H), 3.73-3.65 (m, 8H), 3.58 (m, 18H), 2.43 (s, 3H),2.10-1.98 (m, 2H), 1.94- 1.83 (m, 2H), 1.73-1.65 (m, 3H), 1.59-1.35 (m,3H), 0.93 (s, 9H) 164 I-164 BK FA CI 1110.4ª 12.19 (s, 1H), 9.54 (s,1H), 8.97 (s, 1H), 8.60 (t, J = 5.6 Hz, 1H), 8.37 (s, 1H), 8.16 (s, 1H),7.47- 7.34 (m, 6H), 7.33-7.28 (m, 1H), 6.83 (s, 2H), 4.57 (d, J = 9.6Hz, 1H), 4.55-4.51 (m, 4H), 4.50-4.33 (m, 3H), 4.31- 4.19 (m, 3H), 3.80(s, 6H), 3.69- 3.61 (m, 14H), 2.44 (s, 3H), 2.08-1.80 (m, 4H), 1.67 (s,2H), 1.58-1.36 (m, 3H), 1.35- 1.20 (m, 1H), 0.95 (s, 9H) 165 I-165 BI FACI 1044.5 12.18 (s, 1H), 9.53 (br s, 1H), 9.00-8.90 (m, 1H), 8.59-8.56(m, 1H), 8.15 (s, 1H), 7.49- 7.27 (m, 7H), 6.82 (s, 2H), 4.74- 4.14 (m,7H), 4.02-3.85 (m, 4H), 3.78 (s, 6H), 3.62-3.58 (m, 10H), 2.45-2.41 (m,3H), 2.10-1.19 (m, 12H), 0.98 (d, J = 8.4 Hz, 9H) Variations intemperature and time for Method 14 were as follows: Step 1 was run at50-90 C for anywhere from 4-24 h, Step 3 was run at rt anywhere from2-12 hours, Step 4 was run at rt anywhere from 0.5-2.5 h, Step 5 was runat rt anywhere from 6-16 h, and Step 6 was run at rt for anywhere from0.5-1 h. ªLCMS measure as (M + Na)⁺.

Example 166 (Method 15)4-[2-[2-[2-[2-[4-[[7-[[(1R,2S)-2-aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione,I-166

Step 1—BenzylN-[2-[2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (100 mg, 246 umol, Intermediate EY) in DMF (2 mL) wasadded K₂CO₃ (68.1 mg, 493 umol) and 4-nitro-1H-indole (39.9 mg, 246umol). The reaction mixture was stirred at 100° C. for 3 hours. Oncompletion, the reaction mixture was concentrated in vacuo to removeDMF. The residue was diluted with water (4 mL) and extracted withdichloromethane (2×6 mL). The combined organic layer was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. Theresidue was purified by prep-TLC (PE:EA=1:1) to give the title compound(67.0 mg, 57% yield) as a light yellow oil. LC-MS (ESI⁺) m/z 494.1(M+Na)⁺.

Step 2—BenzylN-[2-[2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of benzylN-[2-[2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate(1.30 g, 2.76 mmol) in EtOH (10 mL) and H₂O (4 mL) was added NH₄Cl (1.48g, 27.6 mmol) and Fe (1.54 g, 27.6 mmol) under nitrogen atmosphere. Thereaction mixture was stirred at 80° C. for 3 hours. On completion, thereaction mixture was filtered and concentrated in vacuo to remove EtOH.The residue was diluted with water (10 mL) and neutralized with sat.NaHCO₃ until the pH=8-9. The residue was diluted with water (10 mL) andextracted with ethyl acetate (2×20 mL). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (1.14 g, 93% yield) as a light yellow oil. LC-MS (ESI⁺) m/z442.1 (M+H)⁺.

Step 3—BenzylN-[2-[2-[2-[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of benzylN-[2-[2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate(1.14 g, 2.58 mmol) and 5,7-dichloro-3H-pyrido[4,3-d]pyrimidin-4-one(550 mg, 2.55 mmol, Intermediate FB) in NMP (10 mL) was added TEA (774mg, 7.65 mmol) under a nitrogen atmosphere. The reaction mixture wasstirred at 140° C. for 1 hour. On completion, the reaction mixture wasconcentrated in vacuo to remove the NMP. The residue was diluted withwater (8 mL) and extracted with ethyl acetate (2×10 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuoto give a residue. The residue was purified by reverse phasechromatography (0.1% FA in water) to give the title compound (800 mg,50% yield) as a yellow solid. ¹H NMR (400 MHz, MeOD) δ 8.26 (dd, J=2.4,6.0 Hz, 1H), 8.15 (s, 1H), 7.34-7.25 (m, 6H), 7.20-7.17 (m, 2H), 6.78(s, 1H), 6.68 (d, J=3.2 Hz, 1H), 5.03 (s, 2H), 4.63 (s, 1H), 4.34 (t,J=5.2 Hz, 2H), 3.83 (t, J=5.2 Hz, 2H), 3.53 (s, 4H), 3.49-3.44 (m, 5H),3.25 (t, J=5.6 Hz, 2H); LC-MS (ESI⁺) m/z 621.1 (M+H)⁺.

Step 4—BenzylN-[2-[2-[2-[2-[4-[[7-[[(1R,2S)-2-aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

A mixture of benzylN-[2-[2-[2-[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate(550 mg, 886 umol) and (1R,2S)-cyclohexane-1,2-diamine (1.01 g, 8.86mmol) in NMP (3 mL) was heated in a microwave at 150° C. for 1.5 hours.On completion, the reaction mixture was filtered and concentrated invacuo to remove the NMP. The residue was purified by prep-HPLC (column:Phenomenex Synergi Max-RP 250*50 mm*10 um; mobile phase: [water (0.225%FA)-ACN]) to give the title compound (200 mg, 32% yield) as a yellowishsolid. LC-MS (ESI⁺) m/z 699.6 (M+H)⁺.

Step 5—Tert-ButylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-7-yl]amino]cyclohexyl]carbamate

To a mixture of benzylN-[2-[2-[2-[2-[4-[[7-[[(1R,2S)-2-aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate(200 mg, 286 umol) in dichloromethane (1 mL) was added (Boc)₂O (62.4 mg,286 umol) under a nitrogen atmosphere. The reaction mixture was stirredat rt for 12 hours. On completion, the reaction mixture was diluted withwater (5 mL) and extracted with dichloromethane (2×10 mL). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuoto give a residue. The residue was purified by prep-TLC(dichloromethane:methanol=20:1) to give the title compound (150 mg, 65%yield) as a yellowish solid. LC-MS (ESI⁺) m/z 799.5 (M+H)⁺.

Step 6—Tert-ButylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]indol-4-yl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-7-yl]amino]cyclohexyl]carbamate

To a mixture of tert-butylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-7-yl]amino]cyclohexyl]carbamate(10.0 mg, 12.5 umol) in EtOAc (5 mL) was added Pd(OH)₂/C (17.5 mg, 12.5umol, 10 wt) under a hydrogen atmosphere (50 psi pressure). The reactionmixture was stirred at rt for 2 hours. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (3.00 mg, 36% yield) as a yellowish solid. LC-MS (ESI⁺) m/z665.3 (M+H)⁺.

Step 7—Tert-ButylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-7-yl]amino]cyclohexyl]carbamate

To a mixture of tert-butylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]indol-4-yl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-7-yl]amino]cyclohexyl]carbamate(50.0 mg, 75.2 umol) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (24.9 mg, 90.2umol, Intermediate R) in DMF (2 mL) was added DIPEA (19.4 mg, 150 umol)under a nitrogen atmosphere. The reaction mixture was stirred at 90° C.for 12 hours. On completion, the reaction mixture was purified byprep-HPLC (Boston Green ODS 150*30 5u; mobile phase: [water (0.225%FA)-ACN]) to give the title compound (18.0 mg, 25% yield) as a yellowsolid. LC-MS (ESI⁺) m/z 921.2 (M+H)⁺.

Step8—4-[2-[2-[2-[2-[4-[[7-[[(1R,2S)-2-aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of tert-butylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-7-yl]amino]cyclohexyl]carbamate(33.0 mg, 35.8 umol) in dichloromethane (8 mL) was added TFA (3.08 g,27.0 mmol). The reaction mixture was stirred at rt for 0.5 hour. Oncompletion, the reaction mixture was concentrated in vacuo to remove thedichloromethane. The residue was purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.1%TFA)-ACN]) to give the title compound I-166 (24.8 mg, 84% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (s, 11H), 11.11 (s, 1H),8.16 (s, 1H), 8.03 (s, 1H), 7.79 (s, 3H), 7.54 (t, J=7.2 Hz, 1H), 7.39(s, 1H), 7.20-7.16 (m, 1H), 7.15-7.06 (m, 3H), 7.02 (d, J=6.0 Hz, 1H),6.56 (s, 2H), 6.06 (s, 1H), 5.05 (d, J=8.0 Hz, 1H), 4.32 (s, 4H), 3.74(s, 2H), 3.64-3.53 (m, 13H), 2.85 (d, J=12.8 Hz, 1H), 2.62-2.59 (m, 1H),2.01 (s, 1H), 1.88-1.57 (m, 6H), 1.47 (s, 2H); LC-MS (ESI⁺) m/z 821.2(M+H)⁺.

Example 167:4-[2-[2-[2-[2-[2-[4-[[7-[[(1R,2S)-2-Aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione,I-167

4-[2-[2-[2-[2-[2-[4-[[7-[[(1R,2S)-2-Aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dioneI-167 was synthesized via Method 15, using Intermediate FC as themesylate in Step 1. Variations in time and temperature were as follows:Step 3 was run at 140° C. for 4 h, Step 5 was run at rt for 7 h, Step 6was run at rt for 4 h with 15 psi pressure of hydrogen, Step 7 was runat 100° C. for 8 h, and Step 8 was run at rt for 1 h. The intermediateformed from Step 5 was purified by prep-HPLC (column: Phenomenex lunaC18 250*50 mm*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 35ACN%-65ACN %, 33 min). Characterization of the final product: ¹H NMR (400MHz, DMSO-d₆) δ 11.7 (s, 1H), 11.1 (s, 1H), 8.18 (br s, 1H), 7.99 (s,1H), 7.78-7.76 (m, 3H), 7.56 (dd, J=7.2, 8.4 Hz, 1H), 7.39 (d, J=3.2 Hz,1H), 7.22-7.16 (m, 1H), 7.16-7.06 (m, 3H), 7.03 (d, J=7.0 Hz, 1H),6.64-6.50 (m, 2H), 6.06 (s, 1H), 5.05 (dd, J=5.6, 12.8 Hz, 1H),4.47-4.17 (m, 4H), 3.67-3.65 (m, 2H), 3.63-3.56 (m, 4H), 3.55-3.53 (m,4H), 3.52-3.47 (m, 10H), 2.96-2.80 (m, 1H), 2.06-1.95 (m, 1H), 1.94-1.55(m, 6H), 1.47-1.45 (m, 2H); LC-MS (ESI⁺) m/z 865.2 (M+H)⁺.

Example 168:4-[2-[2-[2-[4-[[7-[[(1R,2S)-2-Aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione,I-168

4-[2-[2-[2-[4-[[7-[[(1R,2S)-2-Aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dioneI-168 was synthesized via Method 15, using Intermediate FD as themesylate in Step 1. Variations in time and temperature were as follows:Step 1 & 2 were run at 70° C. for 2 h, and Step 6 was run at rt for 6 hwith 15 psi pressure of hydrogen. Characterization of the final product:¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 8.38 (s, 1H), 8.24 (d, J=5.2Hz, 1H), 7.93 (s, 1H), 7.53 (dd, J=7.2, 8.4 Hz, 1H), 7.36 (d, J=3.2 Hz,1H), 7.18-7.12 (m, 1H), 7.11-7.05 (m, 2H), 7.02 (d, J=7.2 Hz, 1H),6.60-6.53 (m, 2H), 6.02 (s, 1H), 5.05 (dd, J 5.6, 12.8 Hz, 1H), 4.31 (t,J 5.2 Hz, 2H), 3.75 (t, J 5.2 Hz, 2H), 3.64-3.58 (m, 10H), 3.40-3.11 (m,2H), 2.91-2.81 (m, 2H), 2.59-2.58 (m, 1H), 2.53-2.52 (m, 1H), 2.46-2.43(m, 1H), 2.05-1.96 (m, 1H), 1.89-1.82 (m, 2H), 1.75-1.57 (m, 4H),1.45-1.33 (m, 2H); LC-MS (ESI⁺) m/z 777.3 (M+H)⁺.

Further Examples Example 169:N-[3-carbamoyl-1-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]azetidin-3-yl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-169

Step1—2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-(2-hydroxyethyl)ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a mixture of 2-[2-[2-(2-aminoethoxy)ethoxy] ethoxy] ethanol (0.60 g,2.61 mmol, 1C8 salt, Intermediate DC) and DIPEA (2.70 g, 20.9 mmol) indioxane (15 mL) was added2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (721 mg, 2.61mmol, Intermediate R). The reaction mixture was stirred at 115° C. for24 hours. On completion, the reaction mixture was concentrated in vacuo.The residue was purified by silica gel chromatography (petroleumether:ethyl acetate=0:1) to give the title compound (0.80 g, 68%˜ yield)as a brown solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.59 (dd,J=3.2, 4.4 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (d, J=7.2 Hz, 1H), 6.61(t, J=5.6 Hz, 1H), 5.06 (dd, J=5.2, 12.8 Hz, in), 4.58-4.56 (m, 1H),3.62 (t, J=5.6 Hz, 2H), 3.59-3.56 (m, 2H), 3.55-3.53 (m, 2H), 3.51-3.44(m, 8H), 3.42-3.38 (m, 2H), 2.95-2.81 (m, 1H), 2.64-2.53 (m, 2H),2.09-2.00 (m, 1H).

Step2—2-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetaldehyde

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione (250 mg, 556 umol) in DCM (10 mL) was added DMP(471 mg, 1.11 mmol) at 0° C. Then the mixture was allowed to warm to rtand stirred for 2 hours. On completion, the reaction mixture wasquenched with saturated NaHCO₃ (10 mL) and saturated Na₂S₂O₃ (10 mL) atrt, and then stirred for an additional 30 minutes. The mixture was thenextracted with DCM (3×20 mL). The combined organic layer was dried withNa₂SO₄, filtered and concentrated in vacuo to give the title compound(226 mg, 91% yield) as a yellow solid. LC-MS (ESI⁺) m/z 448.0 (M+H)⁺.

Step3—N-[3-carbamoyl-1-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]azetidin-3-yl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture ofN-[1-(azetidin-3-yl)-3-carbamoyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide (44.1 mg, 78.2 μmol, TFA salt, Intermediate DB) inDCM (2 mL) was added TEA (11.8 mg, 117 umol), HOAc (9.39 mg, 156 umol)and2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetaldehyde(35.0 mg, 78.2 umol), and the mixture was stirred for 30 minutes at rt.Then NaBH(OAc)₃ (24.8 mg, 117 umol) was added and the mixture wasstirred rt for 16 hours. On completion, the reaction mixture wasconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (column: Kromasil 150*25 mm*10 um; mobile phase: [water(0.225% FA)-ACN]) to give the title compound I-169 (16.4 mg, 21% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 10.93 (s,1H), 8.96 (s, 1H), 8.28-8.20 (m, 2H), 7.76 (s, 1H), 7.68 (t, J=6.4 Hz,1H), 7.61-7.49 (m, 2H), 7.25 (s, 1H), 7.18-7.08 (m, 2H), 7.02 (d, J=6.8Hz, 1H), 6.58 (t, J=5.6 Hz, 1H), 5.07 (dd, J=6.4, 12.8 Hz, 2H),4.25-4.21 (m, 2H), 3.70 (t, J=7.6 Hz, 2H), 3.61 (t, J=5.2 Hz, 2H),3.57-3.47 (m, 14H), 2.92-2.84 (m, 1H), 2.68-2.64 (m, 2H), 2.62-2.54 (m,2H), 2.06-1.99 (m, 1H). LC-MS (ESI⁺) m/z 904.3 (M+Na)⁺.

Example 170:N-[3-carbamoyl-1-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]-4-piperidyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-170

To a mixture ofN-[3-carbamoyl-1-(4-piperidyl)pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(100 mg, 194 umol, HCl salt, Intermediate CX) in DCM (4 mL) was addedTEA (29.4 mg, 291 umol), HOAc (23.3 mg, 388 umol) and2-[2-[2-[2-[[2-(2,6-dioxo-3-npiperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetaldehyde(86.9 mg, 194 umol, synthesized via Steps 1-2 of Example 169) and thereaction was stirred at rt for 30 minutes. Then, NaBH(OAc)₃ (61.7 mg,291 umol) was added to the reaction mixture and the mixture was stirredat rt for an additional 16 hours. On completion, the reaction mixturewas concentrated in vacuo to give a residue. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.1% TFA)-ACN]) to give the title compound I-170 (31.4 mg, 15%yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ=11.11 (s, 1H),10.92 (m, 1H), 9.64 (s, 1H), 8.97 (s, 1H), 8.39 (m, 1H), 8.24 (d, J=5.2Hz, 1H), 7.76 (t, J=5.2 Hz, 1H), 7.61-7.54 (m, 2H), 7.26 (s, 1H),7.20-7.14 (m, 1H), 7.14-7.08 (m, 1H), 7.07-6.99 (m, 1H), 6.57 (s, 1H),5.05 (dd, J=6.4, 12.8 Hz, 1H), 4.80-4.48 (m, 1H), 4.37-4.15 (m, 2H),3.76-3.53 (m, 14H), 3.49-3.37 (m, 4H), 3.35-3.29 (m, 1H), 3.22-3.11 (s,1H), 2.99-2.78 (m, 1H), 2.62-2.51 (m, 2H), 2.41-2.17 (m, 4H), 2.09-1.97(m, 1H). LC-MS (ESI⁺) m/z 910.0 (M+H)⁺.

Example 171:N-[3-carbamoyl-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-171

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (200mg, 332 umol, synthesized via Step 1 of Intermediate CV) in THF (5 mL)and DCM (5 mL) was added DMP (282 mg, 665 umol) at 0° C. and the mixturewas stirred at 0° C. for 2 hours. On completion, the mixture wasquenched with saturated NaHCO₃/Na₂S₂O₃ (1:1, 30 mL) and stirred for anadditional 30 min. The aqueous layer was then separated from the organicand extracted with DCM (3×20 mL). The combined organic solutions werewashed with H₂O (3×20 mL) and brine (20 mL), dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified by reverse phaseflash chromatography (0.1% FA in water) to give the title compound (100mg, 48% yield) as a white solid. LC-MS (ESI⁺) m/z 600.4 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

A mixture of tert-butylN-[4-[4-[[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (40.5 mg, 66.7umol), 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(40.0 mg, 100 umol, synthesized via Steps 1-2 of Example 127) in a mixedsolvent of DCM (5 mL) and THF (5 mL) was added HOAc (6.01 mg, 100 umol)and NaBH(OAc)₃ (42.4 mg, 200 umol). The mixture was stirred at rt for 72hours under nitrogen atmosphere. On completion, the mixture wasconcentrated in vacuo and the residue was purified by reverse phaseflash chromatography (0.1% FA in water) to give the title compound (50.0mg, 76% yield) as a yellow solid. LC-MS (ESI⁺) m/z 988.5 (M+H)⁺.

Step3—N-[3-carbamoyl-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(50.0 mg, 50.6 umol) in THF (5 mL) was added HCl in dioxane (4 N, 2 mL).The mixture was stirred at rt for 2 hours. On completion, the mixturewas concentrated in vacuo, and the residue was purified Pre-HPLC(column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225%FA)-ACN]; B %: 25%-52%, 10 min) to give the title compound I-171 (23.0mg, 51% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s,1H), 9.01 (s, 1H), 8.91 (s, 1H), 8.29-8.21 (m, 2H), 8.03 (s, 1H), 7.89(d, J=8.4 Hz, 2H), 7.76-7.66 (m, 2H), 7.61-7.54 (m, 1H), 7.49 (d, J=8.4Hz, 2H), 7.27 (s, 1H), 7.18 (d, J=5.2 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H),7.02 (d, J=7.2 Hz, 1H), 6.59 (t, J=5.6 Hz, 1H), 5.05 (dd, J=5.2, 12.8Hz, 1H), 4.32-4.19 (m, 2H), 3.81 (s, 2H), 3.72-3.53 (m, 10H), 2.93-2.80(m, 1H), 2.75-2.67 (m, 2H), 2.56-2.53 (m, 3H), 2.09-1.97 (m, 1H); LC-MS(ESI⁺) m/z 888.4 (M+H)⁺.

Example 172:N-[3-carbamoyl-1-[4-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]pentylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-172

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-(5-hydroxypentylcarbamoyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a mixture of4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (100 mg, 162 umol, Intermediate CN) and 5-aminopentan-1-ol (22.0mg, 211 umol) in DMF (5 mL) was added DIPEA (63.0 mg, 487 umol, 85 uL)and HATU (74.0 mg, 195 umol). The mixture was stirred at rt for 2 hours.On completion, the mixture was quenched by water (15 mL), and thenfiltered. The filter cake was dried in vacuo. The residue was purifiedby reverse phase flash chromatography (0.1% FA in water) to give thetitle compound (80.0 mg, 67% yield) as a white solid. LC-MS (ESI⁺) m/z701.3 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-(5-oxopentylcarbamoyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-(5-hydroxypentylcarbamoyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(80.0 mg, 114 umol) in THF (5.0 mL) and DCM (5.0 mL) was added DMP (54.0mg, 125. umol) at 0° C. The mixture was stirred at 0° C. for 2 hours. Oncompletion, the reaction mixture was quenched with saturatedNaHCO₃/Na₂S₂O₃ solution (1:1, 10 mL) and stirred for 30 minutes. Theaqueous layer was separated from the organic and extracted with DCM(3×20 mL). The combined organic layers were washed with H₂O (3×10 mL)and brine (20 mL), dried over MgSO₄, then filtered and concentrated invacuo to give the title compound (80.0 mg, crude) as a yellowish solid.LC-MS (ESI⁺) m/z 599.2 (M+H−100)⁺.

Step 3—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]pentylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a mixture of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-(5-oxopentylcarbamoyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(60.0 mg, 86.0 umol) and4-(2-aminoethylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(34.0 mg, 95.0 umol, HCl salt, Intermediate DJ) in THF (5 mL) was addedAcOH (7.00 mg, 112 umol) and NaBH(OAc)₃ (27.0 mg, 128 umol). The mixturewas stirred at rt for 24 hours under nitrogen atmosphere. On completion,the mixture was concentrated in vacuo. The residue was purified byreverse phase flash chromatography (0.1% FA in water) to give the titlecompound (30.0 mg, 35% yield) as a yellow solid. LC-MS (ESI⁺) m/z 999.0(M+H)⁺.

Step4—N-[3-carbamoyl-1-[4-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]pentylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[5-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethylamino]pentylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(40.0 mg, 40.0 umol) in THF (5 mL) was added HCl in dioxane (4 N, 2 mL).The mixture was stirred at rt for 1 hour. On completion, the mixture wasconcentrated in vacuo, and the residue was purified by Pre-HPLC (column:Boston Green ODS 150*30 5u; mobile phase: [water (0.225% FA)-ACN]; B %:27%-57%, 10 min). to give the title compound I-172 (20.0 mg, 56% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H), 9.03 (d,J=5.6 Hz, 2H), 8.65-8.54 (m, 1H), 8.38-8.23 (m, 2H), 8.16-7.98 (m, 5H),7.82-7.73 (m, 1H), 7.69 (t, J=6.4 Hz, 1H), 7.59 (t, J=7.6 Hz, 1H), 7.27(s, 1H), 7.21-7.12 (m, 2H), 7.05 (d, J=7.2 Hz, 1H), 6.82 (m, 1H), 5.06(dd, J=5.2, 12.8Hz, 1H), 4.32-4.16 (m, 2H), 3.48-3.47 (m, 2H), 3.29 (m,2H), 2.97-2.85 (m, 3H), 2.77-2.66 (m, 2H), 2.64-2.53 (m, 3H), 2.09-1.98(m, 1H), 1.56 (m, 4H), 1.38 (m, 2H); LC-MS (ESI⁺) m/z 899.4 (M+H)⁺.

Example 173:6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxy-2-fluoro-propyl]pyridine-3-carboxamide,I-173

Step1—4-[3-(Dibenzylamino)-2-fluoro-propoxyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of2-(2,6-dioxo-3-piperidyl)-4-hydroxy-isoindoline-1,3-dione (2.00 g, 7.29mmol, synthesized via Step 1 of Intermediate CA) in THF (200 mL) wasadded 3-(dibenzylamino)-2-fluoro-propan-1-ol (1.99 g, 7.29 mmol,Intermediate AH) and PPh₃ (3.83 g, 14.5 mmol). Then DIAD (2.21 g, 10.9mmol) was added to the mixture dropwise at 0° C. The reaction mixturewas allowed to warm to rt and stirred for 12 hours. On completion, thereaction mixture was concentrated in vacuo. The crude product waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10um; mobile phase: [water (0.225% FA)-ACN]; B %: 25ACN %-50ACN %, 30 min,50% min) to give the title compound (2.70 g, 60% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 7.97-7.73 (m, 1H),7.47 (d, J=7.2 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.37-7.21 (m, 8H),7.21-7.08 (m, 2H), 5.21-4.88 (m, 2H), 4.47-4.17 (m, 2H), 3.73-3.53 (m,4H), 3.06-2.75 (m, 3H), 2.70-2.54 (m, 2H), 2.14-1.92 (m, 1H); LC-MS(ESI⁺) m/z 530.0 (M+H)⁺.

Step2—4-(3-Amino-2-fluoro-propoxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione

To a mixture of4-[3-(dibenzylamino)-2-fluoro-propoxy]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(100 mg, 188 umol), Pd(OH)₂/C (60.0 mg, 10 wt %) and Pd/C (60.0 mg, 10wt %) in MeOH (6 mL) was added HCl (1 M, 100 uL) under hydrogenatmosphere (15 psi pressure). The reaction mixture was stirred at rt for18 hours. On completion, the reaction mixture was filtered andconcentrated in vacuo to give the compound (68.0 mg, HCl salt, 95%yield) as a colorless solid. LC-MS (ESI⁺) m/z 350.0 (M+H)⁺.

Step3—6-(5-Cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-N-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxy-2-fluoro-propyl]pyridine-3-carboxamide

To a mixture of4-(3-amino-2-fluoro-propoxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(48.0 mg, 124 umol, HCl salt) in DMF (2 mL) was added6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)pyridine-3-carboxylicacid (64.8 mg, 149 umol, TFA salt, Intermediate L) and DIPEA (96.4 mg,746 umol). Then HATU (70.9 mg, 186 umol) was added to the mixture andthe mixture was stirred at rt for 2 hours. On completion, the reactionmixture was concentrated in vacuo. The crude product was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]) to give the title compound I-173 (24.0 mg, 28%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 9.08(d, J=2.0 Hz, 1H), 9.04 (d, J=2.0 Hz, 1H), 8.95 (t, J=5.6 Hz, 1H),8.72-8.62 (m, 2H), 8.55 (s, 1H), 7.88-7.84 (m, 1H), 7.72 (s, 1H),7.57-7.50 (m, 2H), 5.18-5.01 (m, 2H), 4.69-4.44 (m, 2H), 3.80-3.66 (m,2H), 2.93-2.82 (m, 1H), 2.71-2.56 (m, 3H), 2.09-1.99 (m, 1H), 0.99-0.81(m, 2H), 0.58-0.56 (m, 2H); LC-MS (ESI⁺) m/z 652.2 (M+H)⁺.

Example 174:4-(Cyclopropylamino)-N-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]oxy-2-fluoro-propyl]-6-(1,6-naphthyridin-2-ylamino)pyridine-3-carboxamide,I-174

To a mixture of4-(3-amino-2-fluoro-propoxy)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(100 mg, 259 umol, HCl salt, synthesized via Steps 1-2 of Example 173)and DIPEA (167 mg, 1.30 mmol) in DMF (2 mL) was added4-(cyclopropylamino)-6-(1,6-naphthyridin-2-ylamino)pyridine-3-carboxylicacid (83.3 mg, 259 umol, Intermediate N) and HATU (118 mg, 311 umol).The reaction mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo. Then the residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]) to give the title compound I-174(44.7 mg, 26% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.13(s, 1H), 10.37 (s, 1H), 9.06 (s, 1H), 8.67 (t, J=5.2 Hz, 1H), 8.62-8.56(m, 2H), 8.49 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.18 (s, 1H), 7.86 (t,J=7.6 Hz, 1H), 7.65-7.44 (m, 4H), 5.15-4.98 (m, 2H), 4.60-4.43 (m, 2H),3.76-3.70 (m, 2H), 2.97-2.86 (m, 1H), 2.71-2.56 (m, 3H), 2.08-2.00 (m,1H), 1.01-0.87 (m, 2H), 0.60-0.58 (m, 2H). LC-MS (ESI⁺) m/z 653.2(M+H)⁺.

Example 175:1-[4-(cyclopropylamino)-5-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]-2-pyridyl]pyrazolo[3,4-b]pyridine-5-carbonitrile,I-175

Step 1—Tert-ButylN-[2-[2-[2-[2-[4-[6-chloro-4-(cyclopropylamino)-3-pyridyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butylN-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]carbamate (1.65 g, 5.19mmol, Intermediate BN), CuSO₄ (4.14 mg, 26.0 umol) and sodium(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (10.3mg, 51.9 umol) in a mixed solvent of H₂O (5mL) and t-BuOH (5 mL) wasadded 2-chloro-N-cyclopropyl-5-ethynyl-pyridin-4-amine (500 mg, 2.60mmol, Intermediate DL). The reaction mixture was stirred at 60° C. for 2h. On completion, the mixture was diluted with H₂O (20 mL) and extractedwith EA (2×30 mL). The organic layer was washed with brine (50 mL),dried with Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by reverse phase chromatography (0.1% NH₃ H₂O) to give thetitle compound (1.02 g, 77% yield) as a yellow oil. LC-MS (ESI⁺) m/z511.4 (M+H)⁺.

Step 2—Tert-ButylN-[2-[2-[2-[2-[4-[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-3-pyridyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

Tert-butylN-[2-[2-[2-[2-[4-[6-chloro-4-(cyclopropylamino)-3-pyridyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate (250 mg, 489 umol),1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (177 mg, 1.22 mmol, CAS#1234616-67-1), Pd₂(dba)₃ (179 mg, 196 umol), K₃PO₄ (312 mg, 1.47 mmol)and t-Bu Xphos (83.1 mg, 196 umol) were taken up into a microwave tube.Then dioxane (5 mL) and H₂O (0.5 mL) were added into the microwave tube.The mixture was degassed and purged with nitrogen gas three times, andthen the sealed tube was heated to 100° C. and stirred for 8 hrs undermicrowave. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by pre-HPLC (column:Gemini 150*25 5u; mobile phase: [water (0.05% ammonia hydroxidev/v)-ACN]; B %: 36%-66%) to give the title compound (30 mg, 9.4% yield)as a white solid. LC-MS (ESI⁺) m/z 619.0 (M+H)⁺.

Step3—1-[5-[1-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]triazol-4-yl]-4-(cyclopropylamino)-2-pyridyl]pyrazolo[3,4-b]pyridine-5-carbonitrile

To a solution of tert-butylN-[2-[2-[2-[2-[4-[6-(5-cyanopyrazolo[3,4-b]pyridin-1-yl)-4-(cyclopropylamino)-3-pyridyl]triazol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate(30 mg, 48.5 umol) in DCM (1.5 mL) was added HCl in dioxane (4 M, 1.5mL). The reaction mixture was stirred at rt for 0.5 hr. On completion,the mixture was concentrated in vacuo to give the title compound (26.9mg, 100% yield, HCl salt). LC-MS (ESI⁺) m/z 519.3 (M+H)+

Step4—1-[4-(cyclopropylamino)-5-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]-2-pyridyl]pyrazolo[3,4-b]pyridine-5-carbonitrile

To a solution of1-[5-[1-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]triazol-4-yl]-4-(cyclopropylamino)-2-pyridyl]pyrazolo[3,4-b]pyridine-5-carbonitrile(26.9 mg, 48.5 umol, HCl salt) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (14.7 mg, 53.3umol, Intermediate R) in dioxane (3 mL) was added DIPEA (62.6 mg, 485umol). The reaction mixture was stirred at 115° C. for 60 hrs. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:20%-50%) to give the title compound I-175 (13 mg, 35% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.16-11.03 (m, 1H), 9.06-9.03 (m,1H), 9.03-9.00 (m, 1H), 8.75 (s, 1H), 8.64 (s, 1H), 8.60 (s, 1H),8.44-8.41 (m, 1H), 7.69 (s, 1H), 7.57-7.43 (m, 1H), 7.07-7.02 (m, 1H),7.01-6.97 (m, 1H), 6.57-6.48 (m, 1H), 5.07-5.00 (m, 1H), 4.66-4.59 (m,2H), 3.92-3.86 (m, 2H), 3.58-3.54 (m, 4H), 3.53-3.49 (m, 6H), 3.42-3.40(m, 2H), 2.96-2.81 (m, 1H), 2.62-2.59 (m, 1H), 2.57-2.55 (m, 2H),2.06-1.99 (m, 1H), 0.94-0.87 (m, 2H), 0.65-0.57 (m, 2H); LC-MS (ESI⁺)m/z 775.4 (M+H)⁺.

Example 176:1-[4-(Cyclopropylamino)-5-[1-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]-2-pyridyl]pyrazolo[3,4-b]pyridine-5-carbonitrile,I-176

1-[4-(Cyclopropylamino)-5-[1-[2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]-2-pyridyl]pyrazolo[3,4-b]pyridine-5-carbonitrileI-176 was synthesized as described above for Example 175 except thatIntermediate BQ was used as the azide in Step 1. ¹H NMR (400 MHz, CD₃CN)6 9.07 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.70 (d, J=2.0 Hz, 1H), 8.56 (s,1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.55-7.50(m, 1H), 7.02 (dd, J=4.0, 5.2 Hz, 2H), 6.49-6.40 (m, 1H), 5.00-4.90 (m,1H), 4.63 (t, J=4.8 Hz, 2H), 3.95-3.92 (m, 2H), 3.66-3.55 (m, 8H),3.54-3.50 (m, 10H), 3.45-3.38 (m, 2H), 2.75-2.67 (m, 3H), 2.14-2.13 (m,1H), 1.82-1.77 (m, 1H), 0.95-0.90 (m, 2H), 0.72-0.63 (m, 2H); LC-MS(ESI⁺) m/z 863.4 (M+H)⁺.

Example 177:N-[3-carbamoyl-1-[4-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexa-2,4-diynylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-177

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-(prop-2-ynylcarbamoyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (200 mg, 324 umol, Intermediate CN) and prop-2-yn-1-amine (21.4 mg,389 umol, 24.9 uL) in DMF (5.00 mL) was added HATU (148 mg, 389 umol)and DIPEA (125 mg, 974 umol, 169 uL), and the mixture was stirred at rtfor 1 hr. On completion, the mixture was diluted with H₂O (30 mL) andextracted with EA (3×15 mL). The organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (210 mg, 99% yield) as a white solid. ¹H NMR (400 MHz, MeOD-d₄)δ 11.04 (s, 1H), 9.07 (s, 1H), 9.04-8.99 (m, 2H), 8.63 (d, J=5.2 Hz,1H), 8.22 (s, 1H), 8.12-8.06 (m, 3H), 8.03-7.98 (m, 2H), 7.77-7.73 (m,2H), 4.92-4.82 (m, 2H), 4.08-4.03 (m, 2H), 3.11 (t, J=2.4 Hz, 1H), 1.50(s, 9H).

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexa-2,4-diynylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

A solution of CuI (5.84 mg, 30.6 umol), NiCl₂-6H₂O (1.82 mg, 7.66 umol)and N,N,N′,N′-tetramethylethane-1,2-diamine (356 ug, 3.06 umol) weredissolved in THF (4.00 mL) and stirred at rt for 5 min. Tert-butylN-[4-[4-[[3-carbamoyl-1-[4-(prop-2-ynylcarbamoyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(100 mg, 153 umol) and2-(2,6-dioxo-3-piperidyl)-4-(prop-2-ynylamino)isoindoline-1,3-dione (238mg, 766 umol, Intermediate DN) in THF (4.00 mL) was then added and thereaction mixture was stirred at rt for 16 h. On completion, the reactionmixture was filtered through a pad of celite, and the celite layer waswashed with AcOEt (30 mL). The combined filtrate was concentrated invacuo. The mixture was purified by prep-HPLC (column: Phenomenex SynergiC18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 50%-80%)to give the title compound (25.0 mg, 16% yield) as a yellow solid. LC-MS(ESI⁺) m/z 962.0 (M+H)⁺.

Step3—N-[3-carbamoyl-1-[4-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexa-2,4-diynylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[6-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hexa-2,4-diynylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(20.0 mg, 19.75 umol) in DCM (2.00 mL) was added HCl in dioxane (4 M,2.00 mL), and the mixture was stirred at rt for 30 min. On completion,the mixture was concentrated in vacuo. The mixture was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 40%-70%, 13 min) to give the titlecompound I-177 (2.94 mg, 16% yield, FA) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.11 (s, 11H), 11.01 (s, 1H), 9.14-9.08 (m, 1H), 9.05(s, 1H), 9.03 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.16 (s, 1H), 8.11 (d,J=8.8 Hz, 2H), 8.01 (d, J=8.8 Hz, 2H), 7.78 (s, 1H), 7.72-7.65 (m, 2H),7.27 (s, 1H), 7.20-7.12 (m, 3H), 7.02 (t, J=6.2 Hz, 1H), 5.12-5.02 (m,1H), 4.36-4.30 (m, 2H), 4.28-4.22 (m, 2H), 4.21-4.17 (m, 2H), 2.99-2.81(m, 1H), 2.64-2.56 (m, 2H), 2.09-1.99 (m, 1H), LC-MS (ESI⁺) m/z 862.1(M+H)⁺.

Example 178:N-[3-carbamoyl-1-[4-[7-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hepta-2,4-diynylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-178

N-[3-carbamoyl-1-[4-[7-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]hepta-2,4-diynylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamideI-178 was synthesized as described for Example 177, using IntermediateCN as the acid and prop-2-yn-1-amine as the alkyne in Step 1 andIntermediate DO as the alkyne in Step 2, which was run for 80 h at rt.Characterization of the final product: ¹H NMR (400 MHz, DMSO-d₆) δ 11.10(s, 1H), 11.02 (s, 1H), 9.12 (t, J=5.2 Hz, 1H), 9.06 (d, J=7.6 Hz, 2H),8.26 (d, J=5.2 Hz, 1H), 8.16 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 8.04 (d,J=8.8 Hz, 2H), 7.79 (s, 1H), 7.70 (t, J=6.4 Hz, 1H), 7.62-7.56 (m, 1H),7.28 (s, 1H), 7.19 (s, 1H), 7.19-7.17 (m, 1H), 7.06 (d, J=7.2 Hz, 1H),6.76 (t, J=6.0 Hz, 1H), 5.10-5.04 (m, 1H), 4.28-4.22 (m, 2H), 4.20 (d,J=5.2 Hz, 2H), 3.73-3.45 (m, 2H), 2.95-2.81 (m, 1H), 2.65 (s, 1H),2.61-2.58 (m, 1H), 2.57-2.50 (m, 2H), 2.07-1.97 (m, 1H); LC-MS (ESI⁺)m/z 876.2 (M+H)⁺.

Example 179:N-[3-carbamoyl-1-[4-[8-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]octa-3,5-diynylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-179

N-[3-carbamoyl-1-[4-[8-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]octa-3,5-diynylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamideI-179 was synthesized as described for Example 177, using IntermediateCN as the acid and but-3-yn-1-amine(hydrochloride salt) as the alkyne inStep 1 and Intermediate DO as the alkyne in Step 2, which was run for 80h at rt. Characterization of the final product: ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 11.02 (s, 1H), 9.05 (d, J=6.8 Hz, 2H), 8.83(t, J=5.6 Hz, 1H), 8.26 (d, J=5.6 Hz, 1H), 8.13 (d, J=8.8 Hz, 3H), 8.03(d, J=8.8 Hz, 2H), 7.78 (s, 1H), 7.70 (t, J=6.4 Hz, 1H), 7.62-7.55 (m,1H), 7.28 (s, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.05 (d, J=7.2 Hz, 1H), 6.74(t, J=6.0 Hz, 1H), 5.07 (dd, J=5.2, 13.2 Hz, 1H), 4.30-4.21 (m, 2H),3.53-3.48 (m, 4H), 2.93-2.86 (m, 1H), 2.65-2.60 (m, 6H), 2.03 (d, J=7.6Hz, 1H); LC-MS (ESI⁺) m/z 890.2 (M+H)⁺.

Example 180:N-[3-carbamoyl-1-[4-[[1-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]triazol-4-yl]methylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-180

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[[1-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]triazol-4-yl]methylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of4-(3-azidopropylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(131 mg, 368 umol, Intermediate DP) and tert-butylN-[4-[4-[[3-carbamoyl-1-[4-(prop-2-ynylcarbamoyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate (120mg, 184 umol, synthesized via Step 1 of Example 177) in tert-butanol (4mL) and H₂O (4 mL) was added sodium(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxyl-5-oxo-2H-furan-3-olate (728ug, 3.68 umol) and CuSO₄ (293 ug, 1.84 umol). The reaction mixture washeated to 60° C. and stirred for 12 hours. On completion, the mixturewas concentrated in vacuo to give a residue, and the residue wastriturated with H₂O (50 mL). Then the solid the filtered and dried invacuo. The crude product was purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:48%-78%, 10 min) to give the title compound (60.0 mg, 32% yield) as ayellow solid. LC-MS (ESI⁺) m/z 1009.5 (M+H)⁺.

Step2—N-[3-carbamoyl-1-[4-[[1-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]triazol-4-yl]methylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[1-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]triazol-4-yl]methylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(60.0 mg, 59.5 umol) in DCM (2 mL) was added HCl in dioxane (4 M, 2 mL).The reaction mixture was stirred at rt for 30 minutes. On completion,the reaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u;mobile phase: [water (0.225% FA)-ACN]; B %: 35%-65%, 10 min) to give thetitle compound I-180 (14.2 mg, 24% yield) as yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 11.02 (s, 1H), 9.20-9.20 (m, 1H), 9.05 (d, J=4.4 Hz,2H), 8.26 (d, J=5.2 Hz, 1H), 8.23-7.98 (m, 7H), 7.79 (s, 1H), 7.75-7.68(m, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=4.8 Hz, 1H),7.04 (t, J=8.0 Hz, 2H), 6.72 (m, 1H), 5.05 (dd, J=4.8, 12.8 Hz, 1H),4.54 (d, J=4.8 Hz, 2H), 4.44 (t, J=6.8 Hz, 2H), 4.30-4.20 (m, 2H),3.49-3.43 (m, 2H), 2.95-2.83 (m, 1H), 2.61 (m, 1H), 2.58-2.56 (m, 1H),2.15-2.09 (m, 2H), 2.05-2.00 (m, 1H); LC-MS (ESI⁺) m/z 909.4 (M+H)⁺.

Example 181:N-[3-carbamoyl-1-[4-[2-[1-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]triazol-4-yl]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-181

N-[3-carbamoyl-1-[4-[2-[1-[3-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]propyl]triazol-4-yl]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamideI-181 was synthesized as described for Example 180, using azideIntermediate DP and alkyne tert-butylN-[4-[4-[[1-[4-(but-3-ynylcarbamoyl)phenyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(synthesized via Step 1 of Example 179) in the first step.Characterization of the final product: ¹H NMR (400 MHz, DMSO-d₆) δ 11.11(s, 1H), 11.03 (s, 1H), 9.05 (s, 1H), 9.04 (s, 1H), 8.74 (t, J=5.6 Hz,1H), 8.27 (d, J 5.2 Hz, 1H), 8.15 (s, 1H), 8.12-8.08 (m, 2H), 8.02 (s,2H), 8.00 (s, 1H), 7.79 (s, 1H), 7.74-7.68 (m, 1H), 7.60-7.54 (m, 1H),7.28 (s, 1H), 7.21-7.17 (m, 1H), 7.06-7.01 (m, 2H), 6.69 (t, J=6.0 Hz,1H), 5.10-5.02 (m, 1H), 4.46-4.41 (m, 4H), 4.34-4.28 (m, 2H), 3.57-3.53(m, 2H), 2.95-2.91 (m, 2H), 2.89-2.84 (m, 1H), 2.64-2.59 (m, 2H),2.13-2.08 (m, 2H), 2.07-2.05 (m, 1H); LC-MS (ESI⁺) m/z 923.4 (M+H)⁺.

Example 182:N-[3-carbamoyl-1-[4-[3-[4-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]triazol-1-yl]propylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-182

Step 1—Tert-ButylN-[4-[4-[[1-[4-(3-azidopropylcarbamoyl)phenyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of 3-azidopropan-1-amine (44.3 mg, 324 umol, HCl salt) and4-[4-[[2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-carbamoyl-pyrazol-1-yl]benzoicacid (0.20 g, 324 umol, Intermediate CN) in DMF (4 mL) was added DIPEA(209 mg, 1.62 mmol, 282 uL). The mixture was stirred at rt for 12minutes, and then HATU (148 mg, 389 umol) was added to the mixture. Thereaction mixture was stirred at rt for 2 hours. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by reverse phase chromatography (NH₃H₂O) to givethe title compound (180 mg, 77% yield) as a white solid. LC-MS (ESI⁺)m/z 698.2 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[3-[4-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]triazol-1-yl]propylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of4-(but-3-ynylamino)-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (35.0mg, 107 umol, Intermediate DO) and tert-butylN-[4-[4-[[1-[4-(3-azidopropylcarbamoyl)phenyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(112 mg, 161 umol) in H₂O (1.00 mL) and tert-butanol (3.00 mL) was addedCuSO₄ (171 ug, 1.08 umol) and sodium(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (426ug, 2.15 umol), and the mixture was heated to 60° C. and stirred for 16hr. On completion, the mixture was concentrated in vacuo. The mixturewas purified by prep-HPLC (column: Boston Green ODS 150*30 5u; mobilephase: [water (0.225% FA)-ACN]; B %: 50%-80%, 10 min) to give the titlecompound (30.0 mg, 27% yield) as a yellow solid. LC-MS (ESI⁺) m/z 1045.2(M+Na)⁺.

Step3—N-[3-carbamoyl-1-[4-[3-[4-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]triazol-1-l]propylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[3-[4-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]triazol-1-yl]propylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(30.0 mg, 29.3 umol) in DCM (2.00 mL) was added HCl in dioxane (4 M,5.00 mL), and the mixture was stirred at rt for 30 min. On completion,the mixture was concentrated in vacuo. The mixture was purified byprep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water(0.225% FA)-ACN]; B %: 35%-65%) to give the title compound I-182 (11.8mg, 43% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s,1H), 11.02 (s, 1H), 9.08-9.05 (m, 1H), 9.04 (s, 1H), 8.68 (s, 1H), 8.26(d, J=5.2 Hz, 1H), 8.13 (d, J=3.2 Hz, 2H), 8.10 (s, 1H), 8.03 (s, 1H),8.02-8.01 (m, 2H), 7.79 (s, 1H), 7.74-7.68 (m, 1H), 7.61-7.57 (m, 1H),7.27 (s, 11H), 7.20-7.17 (m, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.03 (d, J=7.2Hz, 1H), 6.75-6.71 (m, 1H), 5.06-5.02 (m, 1H), 4.43-4.39 (m, 2H),4.32-4.21 (m, 2H), 3.64-3.57 (m, 2H), 3.30-3.28 (m, 2H), 2.97-2.93 (m,2H), 2.88-2.84 (m, 1H), 2.62-2.59 (m, 1H), 2.57-2.56 (m, 1H), 2.12-2.07(m, 2H), 2.04-1.98 (m, 1H), LC-MS (ESI⁺) m/z 944.9 (M+Na)⁺.

Example 183:N-[3-carbamoyl-1-[4-[3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]propylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-183

N-[3-carbamoyl-1-[4-[3-[4-[[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]methyl]triazol-1-yl]propylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamideI-183 was synthesized as described above for Example 182, using alkyneIntermediate DN in the second step. Characterization of the finalproduct: ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 11.02 (s, 1H), 9.04(d, J=5.2 Hz, 2H), 8.64 (t, J=5.2 Hz, 1H), 8.26 (d, J=5.2 Hz, 1H),8.15-8.07 (m, 4H), 8.02 (d, J=8.8 Hz, 2H), 7.77 (s, 1H), 7.70 (t, J=6.4Hz, 1H), 7.63-7.55 (m, 1H), 7.28 (s, 1H), 7.21-7.14 (m, 2H), 7.12-7.02(m, 2H), 5.07 (dd, J=5.6, 12.8 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 4.43 (t,J=7.2 Hz, 2H), 4.25 (dd, J=6.4, 9.8 Hz, 2H), 3.29-3.24 (m, 2H),2.95-2.82 (m, 1H), 2.64-2.55 (m, 2H), 2.13-2.00 (m, 3H); LC-MS (ESI⁺)m/z 909.2 (M+H)⁺.

Example 184:T(2R)-3-[(8R)-1-[4-[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]Vethoxy]ethyl]piperazin-1-yl]cyclohexoxy]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]-2-hydroxy-propanamide,I-184

Step1—2-(2,6-Dioxo-3-piperidyl)-4-[2-(2-hydroxyethoxy)ethylamino]isoindoline-1,3-dione

To a solution of 2-(2-aminoethoxy)ethanol (500 mg, 3.53 mmol, HCl salt)in dioxane (15 mL) was added DIPEA (3.65 g, 28.2 mmol) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (1.07 g, 3.88mmol, Intermediate R), and the mixture was stirred at 115° C. for 16 h.On completion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was purified by silica gel chromatography (PE:EA=1:1) to give the title compound (500 mg, 37% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 7.59 (dd, J=7.6, 8.4Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.04 (d, J=6.8 Hz, 1H), 6.61 (t, J 5.6Hz, 1H), 5.06 (dd, J 5.6, 12.8 Hz, 1H), 4.63 (t, J 5.6 Hz, 1H), 3.61 (t,J=5.6 Hz, 2H), 3.55-3.44 (m, 6H), 2.94-2.80 (m, 1H), 2.64-2.52 (m, 2H),2.08-1.97 (m, 1H); LC-MS (ESI⁺) m/z 362.0 (M+H)⁺.

Step2-2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethane-sulfonate

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-(2-hydroxyethoxy)ethylamino]isoindoline-1,3-dione(200 mg, 525 umol) and TEA (159 mg, 1.58 mmol) in DCM (20 mL) was addedMsCl (120 mg, 1.05 mmol) at 0° C. Then the mixture was allowed to warmto rt and stirred for 3 h. On completion, the reaction mixture wasquenched by adding water (30 mL) at 0° C., and then the mixture wasextracted with DCM (3×40 mL). The combined organic layers were washedwith saturated citric acid (2×20 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (200 mg, 86% yield) asa yellow solid. LC-MS (ESI⁺) m/z 440.0 (M+H)⁺.

Step3—T(2R)-3-[(8R)-1-[4-[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]Vethoxy]ethyl]piperazin-1-yl]cyclohexoxy]-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]-2-hydroxy-propanamide

To a solution of(2R)-2-hydroxy-3-[(8R)-1-(4-piperazin-1-ylcyclohexoxy)-7,8-dihydro-6H-cyclopenta[4,5]thieno[1,2-c]pyrimidin-8-yl]propanamide(40 mg, 82.9 umol HCl salt, Intermediate DR) in DMF (3 mL) was addedK₂CO₃ (45.8 mg, 331 umol) and2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl methanesulfonate (48.6 mg, 99.5 umol), and themixture was stirred at 60° C. for 24 h. On completion, the reactionmixture was concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um; mobilephase: [water (0.05% ammonia hydroxide v/v)-ACN]) to give the titlecompound I-184 (23.5 mg, 35% yield, FA salt) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 8.53 (s, 1H), 7.64-7.53 (m, 1H),7.20-7.13 (m, 2H), 7.11 (s, 1H), 7.05 (d, J=6.8 Hz, 1H), 6.60 (t, J=5.6Hz, 1H), 5.20-5.11 (m, 1H), 5.07 (dd, J=5.6, 12.8 Hz, 1H), 3.93 (t,J=6.4 Hz, 1H), 3.60-3.55 (m, 6H), 3.10-2.99 (m, 2H), 2.95-2.87 (m, 2H),2.72-2.56 (m, 3H), 2.48-2.39 (m, 10H), 2.38-2.26 (m, 4H), 2.20-2.01 (m,3H), 1.85-1.82 (m, 2H), 1.63-1.49 (m, 3H), 1.41-1.30 (m, 2H); LC-MS(ESI⁺) m/z 789.3 (M+H)⁺.

Example 185:3-2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(1-(4-(((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide,I-185

Step1—4-(4-(2-(2-((Tert-butoxycarbonyl)(cyclopropylmethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzoic(isopropylcarbonic)anhydride

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl)(cyclopropylmethyl)amino]-4pyridyl]oxazole-4-carbonyl]amio]-3-(trifluoromethyl)-pyrazol-1-yl]benzoicacid (700 mg, 960 umol, Intermediate EG) in THF (10 mL) was added TEA(194 mg, 1.92 mmol). Then, the reaction mixture was cooled to −10° C.Next, isopropyl carbonochloridate (235 mg, 1.92 mmol) was added and thereaction mixture was stirred at −10° C. for 2 hours. On completion, thereaction mixture was filtered. The filtrate was concentrated in vacuo togive the title compound (720 mg, 91% yield) as white solid. LC-MS (ESI⁺)m/z 699.0 (M+H)⁺.

Step 2—Tert-Butyl(cyclopropylmethyl)(4-(4-((1-(4-(hydroxymethyl(phenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

To a solution of isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(trifluoromethyl)pyrazol-1-yl]benzoate(720 mg, 876 umol) in THF (20 mL) was added NaBH₄ (66.3 mg, 1.75 mmol)and water (63.1 mg, 3.50 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 1 hour. On completion, the reaction mixture was quenchedwith water (5 mL) and the mixture was extracted with DCM (3×50 mL). Thecombined organic layer was washed with brine (20 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo to give thetitle compound (520 mg, 99% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 9.06 (s, 1H), 8.88 (s, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.42 (s,1H), 8.36 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.64 (d, J=4.8 Hz, 1H), 7.51(d, J=8.4 Hz, 2H), 4.78 (s, 2H), 3.96 (d, J=7.2 Hz, 2H), 1.59 (s, 9H),0.93-0.81 (m, 1H), 0.47-0.42 (m, 2H), 0.30-0.26 (m, 2H); LC-MS (ESI⁺)m/z 599.2 (M+H)⁺.

Step 3—Tert-Butyl(cyclopropylmethyl)(4-(4-((1-(4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

To a solution oftert-butylN-(cyclopropylmethyl)-N-[4-[4-[[1-[4-(hydroxymethyl)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(320 mg, 535 umol) in DCM (10 mL) was added DMP (454 mg, 1.07 mmol). Thereaction mixture was stirred at rt for 5 hours. On completion, thereaction mixture was quenched with saturated Na₂S₂O₃ (20 mL) andextracted with DCM (3×30 mL). The combined organic layers were washedwith saturated NaHCO₃ (2×20 mL), then washed with brine (30 mL), driedover anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by prep-HPLC (0.1% HCl) to give the title compound(123 mg, 39% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.08(s, 1H), 9.08 (s, 1H), 9.01 (d, J=5.2 Hz, 1H), 8.98 (s, 1H), 8.57 (s,1H), 8.06 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.8 Hz, 2H), 7.45 (s, 1H), 7.39(s, 1H), 3.35 (s, 2H), 1.67 (s, 9H), 1.15-1.05 (m, 1H), 0.78-0.76 (m,2H), 0.45-0.44 (m, 2H).

Step 4—Tert-Butyl(cyclopropylmethyl)(4-(4-((1-(4-(((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate

To a solution of4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(67.8 mg, 154 umol, HCl) in a mixed solvent of DCM (30 mL) and THF (30mL) was added TEA (17.0 mg, 168 umol). The reaction mixture was stirredat rt for 0.5 hour. Then, tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[1-(4-formylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(100 mg, 168 umol, synthesized via Steps 1-2 of Example 127), HOAc (20.1mg, 335 umol, 19.2 uL) and NaBH(OAc)₃ (71.1 mg, 335 umol) were added tothe mixture. The resulting reaction mixture was stirred at rt for 12hours. On completion, the reaction mixture was quenched with water (2mL) and extracted with ethyl acetate (3×50 mL). The combined organiclayers were washed with brine, dried over with anhydrous sodium sulfate,filtered and concentrated in vacuo to give the title compound (150 mg,91% yield) as a yellow solid. LC-MS (ESI⁺) m/z 885.1 (M+H−100)⁺.

Step5—3-2-(2-((Cyclopropylmethyl)amino)pyridin-4-yl)-N-(1-(4-(((2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(150 mg, 152 umol) in DCM (4 mL) was added HCl in dioxane (4 M, 4 mL).The reaction mixture was stirred at rt for 0.5 hour. On completion, thereaction mixture was filtered and concentrated in vacuo to give aresidue. The residue was purified by prep-HPLC (column: PhenomenexSynergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %:10%-40%) to give the title compound I-185 (61.0 mg, 45% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.70 (s, 1H),8.75 (s, 1H), 8.63 (s, 1H), 8.03 (s, 1H), 7.94 (d, J=5.2 Hz, 1H), 7.58(d, J=8.4 Hz, 2H), 7.37-7.30 (m, 1H), 7.27 (d, J=8.4 Hz, 2H), 6.92-6.89(m, 2H), 6.87 (t, J=5.6 Hz, 1H), 6.83-6.77 (m, 2H), 6.38 (t, J=5.6 Hz,1H), 4.83 (dd, J=5.6, 12.8 Hz, 1H), 3.55 (s, 2H), 3.43-3.39 (m, 2H),3.38-3.35 (m, 2H), 3.33-3.30 (m, 2H), 3.29-3.27 (m, 2H), 3.24 (d, J=5.6Hz, 2H), 2.96 (t, J=5.6 Hz, 2H), 2.72-2.59 (m, 1H), 2.48-2.42 (m, 2H),2.38-2.31 (m, 1H), 2.30-2.85 (m, 1H), 1.83-1.76 (m, 1H), 0.89-0.81 (m,1H), 0.27-0.21 (m, 2H), 0.01 (m, 2H); LC-MS (ESI⁺) m/z 885.1 (M+H)⁺.

Example 186:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[1-[3-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]oxazole-4-carboxamide,I-186

Step 1—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[1-(3-formylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[1-[3-(hydroxymethyl)phenyl]-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (320 mg,534 umol. Intermediate EI) in DCM (8.00 mL) was added DMP (105 mg, 249umol), and the mixture was stirred at 25° C. for 20 hours. Oncompletion, the mixture was quenched with saturated Na₂S₂O₃ (2×30 mL)and extracted with DCM (30 mL). The organic layer was washed withsaturated NaHCO₃ (2×30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (280 mg, 87%˜ yield) asa red solid, ¹H NMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 9.01 (s, 1H), 8.92(s, 1H), 8.46 (d, J=5.2 Hz, in), 8.36 (s, 1H), 8.30 (s, 1H), 8.22 (s,1H), 8.03-7.98 (m, 1H), 7.83 (d, J=7.6 Hz, in), 7.66-7.60 (m, 1H), 7.56(dd, J=1.2, 5.2 Hz, 1H), 3.88 (d, J=7.2 Hz, 2H), 1.51 (s, 9H), 1.18-1.11(m, 1H), 0.39-0.34 (m, 2H), 0.24-0.20 (m, 2H).

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[1-[3-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[1-(3-formylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (100 mg, 167umol) and 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(88.6 mg, 201 umol, HCl, synthesized via Steps 1-2 of Example 127) inTHF (30.0 mL) was added KOAc (32.9 mg, 335 umol) and NaBH(OAc)₃ (71.0mg, 335 umol). The mixture was stirred at rt for 16 hours. Oncompletion, the mixture was quenched with water (2 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic layers were washedwith brine, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The mixture was purified by reverse phaseprep-HPLC (0.1% FA) to give the title compound (80.0 mg, 48% yield) as ayellow solid. LC-MS (ESI⁺) m/z 985.4 (M+H)⁺.

Step3-2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[1-[3-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[1-[3-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(80.0 mg, 81.2 umol) in DCM (2.00 mL) was added HCl in dioxane (4 M,2.00 mL). The mixture was stirred at rt for 15 minutes. On completion,the mixture was concentrated in vacuo. The mixture was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 10%-40%, 10 min) to give the titlecompound I-186 (41.2 mg, 57% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.11 (s, 1H), 9.92 (s, 1H), 8.98 (s, 1H), 8.88 (s, 1H), 8.23(s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J=8.4 Hz, 1H),7.55 (dd, J=7.2, 8.4 Hz, 1H), 7.48 (t, J=8.0 Hz, 1H), 7.37 (d, J=7.6 Hz,1H), 7.13-7.08 (m, 3H), 7.06-7.01 (m, 2H), 6.64-6.54 (m, 1H), 5.08-5.01(m, 1H), 3.82 (s, 2H), 3.59-3.53 (m, 10H), 3.23-3.16 (m, 2H), 2.92-2.84(m, 1H), 2.69-2.66 (m, 2H), 2.62-2.58 (m, 1H), 2.57-2.55 (m, 1H),2.06-1.94 (m, 1H), 1.12-1.01 (m, 1H), 0.50-0.43 (m, 2H), 0.27-0.20 (m,2H); LC-MS (ESI⁺) m/z 885.1 (M+H)⁺.

Example 187:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[1-[4-[[2-[2-[3-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-5-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]-3-(trifluoromethyl)pyrazol-4-yl]oxazole-4-carboxamide,I-187

To a solution of5-[3-[2-(2-aminoethoxy)ethoxy]propyl]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(45.0 mg, 102 umol, HCl salt, Intermediate CQ) and2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[1-(4-formylphenyl)-3-(trifluoromethyl)pyrazol-4-yl]oxazole-4-carboxamide(54.5 mg, 102 umol, synthesized via Steps 1-3 of Example 185) in THF (10mL) was added KOAc (20.1 mg, 205 umol) and the reaction mixture wasstirred for 30 minutes at rt. Then NaBH(OAc)₃ (54.2 mg, 256 umol) wasadded in portions and the mixture was stirred at rt for 2 hours. ThenHOAc (1.23 g, 20.5 mmol, 1.17 mL) was added and the mixture was stirredfor 30 minutes. Finally, more NaBH(OAc)₃ (54.2 mg, 256 umol) was addedand the reaction was stirred for 2 hours. On completion, the reactionmixture was quenched by addition water (2 mL), and then concentrated invacuo. The residue was purified by prep-HPLC (reserve phase(ACN-water/0.1% FA)) and lyophilized to give the title compound I-187(21.5 mg, 22% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.12(s, 1H), 9.92 (s, 1H), 8.98 (s, 1H), 8.86 (s, 1H), 8.26 (s, 1H), 8.16(d, J 5.2 Hz, 1H), 7.84-7.79 (m, 3H), 7.77 (s, 1H), 7.70 (d, J 7.6 Hz,1H), 7.51 (d, J 8.4 Hz, 2H), 7.14-7.07 (m, 2H), 7.06-7.02 (m, 1H), 5.14(dd, J=5.6, 13.2 Hz, 1H), 3.79 (s, 2H), 3.53-3.50 (m, 4H), 3.41-3.75 (m,2H), 3.19 (t, J=6.4 Hz, 2H), 2.95-2.76 (m, 4H), 2.71-2.60 (m, 4H),2.59-2.53 (m, 2H), 2.08-2.01 (m, 1H), 1.90-1.81 (m, 2H), 1.11-1.04 (m,1H), 0.49-0.43 (m, 2H), 0.26-0.20 (m, 2H); LC-MS (ESI⁺) m/z 884.0(M+H)⁺.

Example 188:N-(3-carbamoyl-1-(4-((5-(2-((5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)pentyl)oxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide,I-188

Step1—N-(3-carbamoyl-1-(4-((5-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

5-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)ethoxy)pentan-1-amine (122mg, 0.38 mmol, Intermediate EV) was dissolved in DMF (2 mL).4-(3-carbamoyl-4-(2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamido)-1H-pyrazol-1-yl)benzoicacid (198 mg, 0.38 mmol, Intermediate ET), HATU (159 mg, 0.42 mmol) andN,N-diisopropylethylamine (0.13 mL, 0.76 mmol) were then added and thereaction mixture was stirred at rt for 16 h. The reaction mixture wasthen diluted with a saturated aqueous solution of NaHCO₃ and extractedwith Ethyl Acetate (3 times). The combined organic was washed withwater, dried over magnesium sulfate and filtered. The mixture was thenconcentrated in vacuo and the residue was purified by silica gelchromatography (gradient of 0-10% methanol in dichloromethane) to givethe title compound (161 mg, 50%) as a yellow powder.

Step2—N-(3-carbamoyl-1-(4-((5-(2-(4-hydroxybutoxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

N-(3-carbamoyl-1-(4-((5-(2-(4-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide(161 mg, 0.19 mmol) was dissolved in a 1.25 M solution of HCl inmethanol (1.6 mL) and the reaction mixture was stirred at rt for 2hours. The reaction mixture was then concentrated in vacuo to give thetitle compound as an orange solid (142 mg, quantitative yield). LC-MS(ESI⁺) m/z 731.4 (M+H)⁺.

Step3—N-(3-carbamoyl-1-(4-((5-(2-(4-oxobutoxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

To a suspension ofN-(3-carbamoyl-1-(4-((5-(2-(4-hydroxybutoxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide(142 mg, 0.19 mmol) in acetone (10 mL) was added 2-iodoxybenzoic acid(156 mg, 0.57 mmol) and the reaction mixture was heated at 55° C. in asealed tube for 16 h. The reaction mixture was then quenched with asaturated aqueous solution of NaHCO₃ and extracted with Ethyl Acetate.The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo to give the title compound which was used directlyin the subsequent step. LC-MS (ESI⁺) m/z 729.4 (M+H)⁺.

Step4—N-(3-carbamoyl-1-(4-((5-(2-((5-(((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)pentyl)oxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide

N-(3-carbamoyl-1-(4-((5-(2-(4-oxobutoxy)ethoxy)pentyl)carbamoyl)phenyl)-1H-pyrazol-4-yl)-2-(2-((2,2,2-trifluoroethyl)amino)pyridin-4-yl)oxazole-4-carboxamide(177 mg, 0.24 mmol) and(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)-phenyl]methyl]pyrrolidine-2-carboxamide(125 mg, 0.29 mmol, Intermediate CI) was dissolved in a mixture ofmethanol (1.4 mL) and dichloromethane (0.8 mL) and stirred for 5 minutesbefore the addition of borane pyridine complex (49 μL, 0.48 mmol). Thereaction mixture was stirred at rt until completion. The reactionmixture was then concentrated in vacuo, diluted in Ethyl Acetate andpartitioned with a saturated aqueous solution of NaHCO₃. The precipitatewas filtered off and the mixture was extracted with Ethyl Acetate (3times). The combined organic layer was concentrated in vacuo.Purification with silica gel chromatography (gradient mixture of 0-60%methanol in dichloromethane) gave 74 mg of the impure product. A secondpurification was performed using silica gel chromatography (gradient of10-40% methanol in dichloromethane) to give the title compound I-188 (20mg, 7%) as a yellow powder. ¹H NMR (400 MHz, DMSO): δ 11.00 (s; 1H);9.02 (d; J=2.46 Hz; 2H); 8.95-8.96 (m; 1H); 8.52-8.56 (m; 2H); 8.24 (d;J=5.29 Hz; 1H); 8.12 (s; 1H); 8.08 (d; J=8.51 Hz; 2H); 7.99 (d; J=8.39Hz; 2H); 7.76 (s; 1H); 7.68 (t; J=6.53 Hz; 1H); 7.34-7.42 (m; 4H); 7.25(s; 1H); 7.16 (d; J=5.39 Hz; 1H); 5.02 (d; J=3.19 Hz; 1H); 4.50 (t;J=8.16 Hz; 1H); 4.30-4.39 (m; 3H); 4.17-4.28 (m; 4H); 3.48-3.57 (m; 2H);3.44 (s; 4H); 3.20-3.40 (m; 6H); 2.99 (s; 1H); 2.41-2.43 (m; 4H);2.22-2.32 (m; 2H); 1.41-1.57 (m; 6H); 1.28-1.37 (m; 6H); 0.88 (s; 9H).LC-MS (ESI⁺) m/z [M+2H]²⁺: 572.3.

Example 189:(2S,4R)-1-[(2S)-2-[[2-[2-[2-[4-[[7-[[(1R,2S)-2-aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide,I-189

Step 1—Ethyl 2-[2-[24(4-nitroindol-1-yl)ethoxy]ethoxy]acetate and2-[2-[2-(4-nitroindol-1-yl) ethoxyl]ethoxy] acetic Acid

To a solution of 4-nitro-1H-indole (649 mg, 4.01 mmol) and Cs₂CO₃ (3.26g, 10.0 mmol) in DMF (15.0 mL) was added ethyl2-[2-(2-methylsulfonyloxyethoxy)ethoxy]acetate (1.30 g, 4.81 mmol,synthesized via Steps 1-2 of Intermediate BM), then the reaction mixturewas stirred at 80° C. for 12 hours. On completion, the reaction mixturewas concentrated in vacuo to give a residue, the residue was dilutedwith water (40 mL) and acidified with the saturated citric acid aqueoussolution (10 mL) until the pH=2. Then the mixture was extracted with EA(30 mL×5). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo to give a mixture of ethyl2-[2-[2-(4-nitroindol-1-yl) ethoxy]ethoxy]acetate (800 mg, 59% yield)and 2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]acetic acid (500 mg, 40%yield). LC-MS (ESI⁺) m/z 359.0 (M+Na)⁺ and LC-MS (ESI⁺) m/z 309.0(M+H)⁺.

Step 2—Ethyl 2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]acetate

To a mixture of ethyl 2-[2-[2-(4-nitroindol-1-yl) ethoxy]ethoxy]acetate(800 mg, 2.38 mmol) and 2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]aceticacid (500 mg, 1.62 mmol) in EtOH (10.0 mL) was added SOCl₂ (1.00 g, 8.44mmol), and the reaction mixture was stirred at 80° C. for 2 hours. Oncompletion, the reaction mixture was concentrated in vacuo to give aresidue. The residue was diluted water (15 mL) and extracted with EA (20mL×3). The combined organic layers were dried over sodium sulfate,filtered and concentrated in vacuo to give the title compound (950 mg,66% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.12 (d, J=8.0 Hz, 1H), 7.71 (d,J=8.0 Hz, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.25 (d, J=1.6 Hz, 1H), 7.22 (d,J=3.2 Hz, 1H), 4.38 (t, J=5.6 Hz, 2H), 4.19 (q, J=7.2 Hz, 2H), 4.01 (s,2H), 3.82 (t, J=5.2 Hz, 2H), 3.64-3.60 (m, 2H), 3.59-3.54 (m, 2H), 1.26(t, J=7.2 Hz, 3H); LC-MS (ESI⁺) m/z 337.1 (M+H)⁺.

Step 3—Ethyl 2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]acetate

To a solution of ethyl 2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]acetate(950 mg, 2.82 mmol) in EA (12.0 mL) was added Pd/C (600 mg, 2.82 mmol)under nitrogen atmosphere. The suspension was degassed and purged withhydrogen gas 3 times. The mixture was stirred under hydrogen atmosphere(15 psi pressure) at rt for 2 hours. On completion, the reaction mixturewas filtered and concentrated in vacuo to give the title compound (850mg, 98% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=3.6 Hz, 1H), 7.03(t, J=8 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.41-6.39 (m, 2H), 4.27 (t,J=6.0 Hz, 2H), 4.23 (q, J=7.2 Hz, 2H), 4.09 (s, 2H), 3.91 (s, 2H), 3.81(t, J=6.0 Hz, 2H), 3.69-3.64 (m, 2H), 3.60-3.56 (m, 2H), 1.30 (t, J=7.2Hz, 3H); LC-MS (ESI⁺) m/z 307.1 (M+H)⁺.

Step 4—Ethyl2-[2-[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]acetate

To a solution of ethyl 2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]acetate(500 mg, 1.63 mmol) and 5,7-dichloro-3H-pyrido[4,3-d]pyrimidin-4-one(352 mg, 1.63 mmol, Intermediate FB) in NMP (4 mL) was added TEA (329mg, 3.26 mmol), and the reaction mixture was stirred at 140° C. for 2hours. On completion, the reaction mixture was concentrated in vacuo togive a residue. The residue was purified by silica gel chromatography(PE/EA=1/2) to give the title compound (500 mg, 63% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (s, 1H), 11.75 (s, 1H), 8.31(s, 1H), 8.17 (d, J=7.6 Hz, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.28 (d, J=8.0Hz, 1H), 7.17 (t, J=8.0 Hz, 2H), 6.91 (s, 1H), 6.56 (d, J=3.2 Hz, 1H),4.36 (t, J=5.6 Hz, 2H), 4.10 (q, J=7.2 Hz, 2H), 4.05 (s, 2H), 3.76 (t,J=5.2 Hz, 2H), 3.53 (d, J=3.6 Hz, 4H), 1.18 (t, J=7.2 Hz, 3H); LC-MS(ESI⁺) m/z 486.0 (M+H)⁺.

Step5-2-[2-[2-[4-[(7-Chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]aceticAcid

To a solution of ethyl2-[2-[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]acetate (260 mg, 535 umol) in THF (3.00 mL) and H₂O (3.00mL) was added LiOH (51.2 mg, 2.14 mmol), and the mixture was stirred atrt for 2 hours. On completion, the mixture was acidified with 1N HClsolution (1 mL) until the pH=3, then diluted with water (5 mL) andextracted with DCM (50 mL×3). The combined organic layers were driedover sodium sulfate, filtrated and concentrated in vacuo to give theproduct (230 mg, 93% yield) as a light yellow solid. LC-MS (ESI⁺) m/z458.1 (M+H)⁺.

Step6—(2S,4R)-1-[(2S)-2-[[2-[2-[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

A solution of2-[2-[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]acetic acid (180 mg, 393 umol) in DMF (3.00 mL) was cooled to 0°C. Then,(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(166 mg, 357 umol, HCl salt, Intermediate CI), DIPEA (277 mg, 2.14 mmol)and HATU (163 mg, 428 umol) were added. Then the mixture was stirred atrt for 6 hours. On completion, the reaction mixture was concentrated invacuo to remove the DMF. The residue was diluted with water (40 mL) andextracted with EA (40 mL×3). The combined organic layers were dried oversodium sulfate and concentrated in vacuo to give a residue. The residuewas purified by silica gel chromatography (reverse phase (0.1% FA)) togive the title compound to (255 mg, 81% yield) as light yellow solid.LC-MS (ESI⁺) m/z 870.4 (M+H)⁺.

Step7—(2S,4R)-1-[(2S)-2-[[2-[2-[2-[4-[[7-[[(1R,2S)-2-aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

A mixtureof(2S,4R)-1-[(2S)-2-[[2-[2-[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthi-azol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(100 mg, 114 umol) and (1R,2S)-cyclohexane-1,2-diamine (52.4 mg, 459umol) in NMP (2 mL) were placed in a sealed tube and stirred at 140° C.for 1.5 hours under microwave. On completion, the mixture was purifiedby prep-HPLC (column: Boston Green ODS 150*30 5u; mobile phase: [water(0.225% FA)-ACN]) to give the title compound I-189 (21.0 mg, 18% yield)as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, 1H), 8.94 (s,1H), 8.61 (t, J=5.6 Hz, 1H), 8.35 (s, 2H), 8.30-8.24 (m, 1H), 7.91 (s,1H), 7.47-7.30 (m, 6H), 7.17 (d, J=8.0 Hz, 1H), 7.08 (t, J=5.6 Hz, 1H),6.57 (d, J=3.2 Hz, 1H), 6.00 (s, 1H), 4.60 (d, J=9.6 Hz, 1H), 4.46 (t,J=8.0 Hz, 1H), 4.39-4.31 (m, 4H), 4.27-4.22 (m, 1H), 3.99-3.94 (m, 2H),3.77 (t, J=5.4 Hz, 2H), 3.71-3.65 (m, 2H), 3.63-3.60 (m, 2H), 3.58-3.56(m, 2H), 3.54-3.53 (m, 2H), 2.53-2.52 (m, 2H), 2.41 (s, 3H), 2.07 (s,1H), 1.97-1.87 (m, 2H), 1.80-1.74 (m, 2H), 1.68-1.60 (m, 4H), 1.44-1.36(m, 2H), 1.00-0.92 (s, 9H). LC-MS (ESI⁺) m/z 948.3 (M+H)⁺.

Example 190:(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[4-[[7-[[(1R,2S)-2-aminocyclohexyl]amino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanol]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide,I-190

The title compound I-190 was synthesized as described in the methodabove for Example 189, using Intermediate BK as the mesylate in thefirst step which was run at 80° C. for 8 h. Time and temperaturevariations were as follows: Step 2 was run at 80° C. for 6 h, Step 3 wasrun at rt for 6 h and Step 7 was run at 150° C. for 1.5 h.Characterization data of the final compound: ¹H NMR (400 MHz, DMSO-d₆) δ11.25 (s, 1H), 9.18 (s, 1H), 9.09 (s, 1H), 8.68 (t, J=5.6 Hz, 1H),8.30-8.28 (m, 3H), 8.20 (s, 11H), 8.10 (d, J=7.2 Hz, 1H), 7.46-7.35 (m,6H), 7.24 (d, J=7.6 Hz, 1H), 7.12 (t, J 7.6 Hz, 1H), 6.51 (d, J=2.8 Hz,1H), 6.33 (s, 1H), 4.44-4.17 (m, 10H), 3.90 (s, 2H), 3.79-3.37 (m, 18H),2.44 (s, 3H), 2.13-1.83 (m, 4H), 1.79-1.56 (m, 4H), 1.48-1.34 (m, 2H),0.92 (s, 9H); LC-MS (ESI⁺) m/z 1036.3 (M+H)⁺.

Example 191:N-[2-[[5-chloro-2-[5-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4-methoxy-2-methyl-anilino]pyrimidin-4-yl]amino]-5-methoxy-phenyl]methanesulfonamide,I-191

Step1—N-[2-[[2-(5-benzyloxy-4-methoxy-2-methyl-anilino)-5-chloro-pyrimidin-4-yl]amino]-5-methoxy-phenyl]methanesulfonamide

A mixture ofN-[2-[(2,5-dichloropyrimidin-4-yl)amino]-5-methoxy-phenyl]methanesulfonamide(1.00 g, 2.75 mmol, Intermediate FE),5-benzyloxy-4-methoxy-2-methyl-aniline (735 mg, 3.03 mmol, synthesizedvia Steps 1-3 of Intermediate FE), HCl in dioxane (4 M, 996 uL) and IPA(10 mL) was heated in a microwave at 120° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby prep-column chromatography to give the title compound (1.50 g, 95%yield) as a yellowish solid. LC-MS (ESI⁺) m/z 570.0 (M+H)⁺.

Step2—N-[2-[[5-chloro-2-(5-hydroxy-4-methoxy-2-methyl-anilino)pyrimidin-4-yl]amino]-5-methoxy-phenyl]methanesulfonamide

To a mixture ofN-[2-[[2-(5-benzyloxy-4-methoxy-2-methyl-anilino)-5-chloro-pyrimidin-4-yl]amino]-5-methoxyphenyl]methanesulfonamide(2.50 g, 4.39 mmol) in DCM (20 mL) was added BCl₃·DCM (1 M, 26.34 mL)dropwise at rt. Then the reaction mixture was stirred at rt for 2 hours.On completion, the reaction mixture was concentrated in vacuo. Theresidue was washed with sat.NaHCO₃ (100 mL) and extracted with DCM(3×200 mL). Then the combined organic layer was dried with Na₂SO₄,filtered and concentrated in vacuo. The residue was purified byprep-column chromatography to give the title compound (1.70 g, 80%yield) as a pale solid. LC-MS (ESI⁺) m/z 480.1 (M+H)⁺.

Step 3—BenzylN-[2-[2-[2-[2-[2-[5-[[5-chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture ofN-[2-[[5-chloro-2-(5-hydroxy-4-methoxy-2-methyl-anilino)pyrimidin-4-yl]amino]-5-methoxy-phenyl]methanesulfonamide(150 mg, 312 umol) and 2-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethyl methanesulfonate (168 mg, 375umol, Intermediate FC) in DMF (10 mL) was added K₂CO₃ (64.7 mg, 468umol). Then the reaction mixture was stirred at 100° C. for 12 hours. Oncompletion, the reaction mixture was concentrated in vacuo. Then thereaction mixture was purified by reverse phase chromatography to givethe title compound (120 mg, 46% yield) as a yellowish oil. LC-MS (ESI⁺)m/z 833.4 (M+H)⁺.

Step4—N-[2-[[2-[5-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-4-methoxy-2-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]-5-methoxy-phenyl]methanesulfonamide

To a mixture of benzylN-[2-[2-[2-[2-[2-[5-[[5-chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethyl]carbamate(90.0 mg, 108 umol) in ACN (500 uL) was added 40% HBr solution (4.47 g,55.2 mmol, 3.00 mL). Then the reaction mixture was stirred at 60° C. for6 hours. On completion, the reaction mixture was concentrated in vacuo.The residue was washed with sat.NaHCO₃ (30 mL) and extracted with DCM(3×50 mL). The organic layer was dried with Na₂SO₄, filtered andconcentrated in vacuo to give the title compound (55.0 mg, 62% yield) asa yellowish oil. LC-MS (ESI⁺) m/z 699.1 (M+H)⁺.

Step5—N-[2-[[5-chloro-2-[5-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4-methoxy-2-methyl-anilino]pyrimidin-4-yl]amino]-5-methoxy-phenyl]methanesulfonamide

To a mixture ofN-[2-[[2-[5-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-4-methoxy-2-methyl-anilino]-5-chloro-pyrimidin-4-yl]amino]-5-methoxy-phenyl]methanesulfonamide(50.0 mg, 71.5 umol) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (23.7 mg, 85.8umol, Intermediate R) in DMF (2 mL) was added DIPEA (27.7 mg, 214 umol,37.4 uL). Then the reaction mixture was stirred at 90° C. for 12 hours.On completion, the reaction mixture was concentrated in vacuo. Theresidue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u;mobile phase:[water (0.225% FA)-ACN]) to give the title compound I-191(14.0 mg, 19% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11(s, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.81(d, J=8.8 Hz, 1H), 7.62-7.54 (m, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.04 (d,J=7.2 Hz, 1H), 6.90 (s, 1H), 6.83 (d, J=2.8 Hz, 1H), 6.80 (s, 1H), 6.60(t, J=5.6 Hz, 1H), 6.31 (s, 1H), 5.08-4.99 (m, 1H), 3.93-3.86 (m, 2H),3.76 (s, 3H), 3.68 (s, 3H), 3.67-3.63 (m, 3H), 3.62-3.58 (m, 4H),3.56-3.52 (m, 8H), 3.50 (s, 3H), 3.05 (s, 1H), 2.95-2.84 (m, 2H), 2.79(s, 3H), 2.09 (s, 3H), 2.04-2.00 (m, 1H); LC-MS (ESI⁺) m/z 955.4 (M+H)⁺.

Example 192:(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[5-[[5-chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide,I-192

Step1—Ethyl2-[2-[2-[2-[2-(2-methoxy-4-methyl-5-nitro-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of 2-methoxy-4-methyl-5-nitro-phenol (500 mg, 2.73 mmol,Intermediate FF) and K₂CO₃ (1.13 g, 8.19 mmol) in DMF (15 mL) was addedethyl 2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy] ethoxy]ethoxy]acetate (978 mg, 2.73 mmol, Intermediate BK) at rt. The reactionmixture was then heated to 100° C. and stirred for 1 hour. Oncompletion, the reaction mixture was poured into water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined layer was washedwith brine (50 mL), dried over Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to give a residue. The residue was purified bysilica gel chromatography (petroleum ether:ethyl acetate=5:1) to givethe title compound (900 mg, 74% yield) as a yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 7.73 (s, 1H), 6.71 (s, 1H), 4.27-4.18 (m, 4H), 4.15 (s, 2H),3.94 (s, 3H), 3.93-3.88 (m, 2H), 3.76-3.66 (m, 12H), 2.62 (s, 3H), 1.29(t, J=7.2 Hz, 3H).

Step 2—Ethyl2-[2-[2-[2-[2-(5-amino-2-methoxy-4-methyl-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of ethyl2-[2-[2-[2-[2-(2-methoxy-4-methyl-5-nitro-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (550 mg, 1.23 mmol) in EtOAc (10 mL) was added Pd/C (450mg, 10 wt %) under hydrogen atmosphere (15 psi pressure). The reactionmixture was stirred at rt for 12 hours. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (470 mg, 91% yield) as a light yellow oil. LC-MS (ESI⁺) m/z416.2 (M+H)⁺.

Step 3—Isopropyl2-[2-[2-[2-[2-[5-[[5-chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a mixture of ethyl2-[2-[2-[2-[2-(5-amino-2-methoxy-4-methyl-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (470 mg, 1.13 mmol) andN-[2-[(2,5-dichloropyrimidin-4-yl)amino]-5-methoxy-phenyl]methanesulfonamide (410 mg, 1.13 mmol, Intermediate FE) in IPA (10 mL)was added HCl in dioxane (4 M, 409 uL). The reaction mixture was stirredat 120° C. for 1 hour in a microwave. On completion, the reactionmixture was concentrated in vacuo to remove the IPA. The residue waspoured into 5 mL of water and basified with sat. Na₂CO₃ until thepH=7-8, then the mixture was extracted with dichloromethane (2×10 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (dichloromethane:methanol=100:1) to give the titlecompound (226 mg, 26% yield) as a light yellow oil. LC-MS (ESI⁺) m/z742.1 (M+H)⁺.

Step4-2-[2-[2-[2-[2-[5-[[5-Chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a mixture of ethyl2-[2-[2-[2-[2-[5-[[5-chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate(226 mg, 304 umol) in THF (4 mL) and H₂O (2 mL) was added LiOH H₂O (51.1mg, 1.22 mmol). The reaction mixture was stirred at rt for 12 hours. Oncompletion, the reaction mixture was concentrated in vacuo to removeTHF. The residue was poured into 5 mL of water and acidified with HCluntil the pH=6-7, then the mixture was extracted with dichloromethane(3×10 mL). The combined organic layers were dried over Na₂SO4, filteredand concentrated in vacuo to give the title compound (162 mg, 74% yield)as a yellowish solid. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 7.92 (s,1H), 7.70 (s, 1H), 7.38 (d, J=8.8 Hz, 1H), 6.99 (s, 1H), 6.94 (d, J=2.4Hz, 1H), 6.70 (dd, J=2.8, 8.8 Hz, 1H), 6.64 (s, 1H), 4.12 (s, 2H),3.82-3.80 (m, 8H), 3.75-3.71 (m, 4H), 3.69-3.61 (m, 10H), 2.87 (s, 3H),2.10 (s, 3H); LC-MS (ESI⁺) m/z 714.1 (M+H)⁺.

Step5—(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[5-[[5-chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a mixture of2-[2-[2-[2-[2-[5-[[5-chloro-4-[2-(methanesulfonamido)-4-methoxy-anilino]pyrimidin-2-yl]amino]-2-methoxy-4-methyl-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticacid (80.0 mg, 112 umol) and(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (48.2 mg, 103 umol HCl,Intermediate CI) in DMF (3 mL) was added HATU (51.1 mg, 134 umol) andDIPEA (72.3 mg, 560 umol) under nitrogen atmosphere. The reactionmixture was stirred at rt for 3.5 hours. On completion, the reactionmixture was purified prep-HPLC (Gemini 150*25 5u; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]) to give the title compound I-192(24.5 mg, 19% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.00(s, 1H), 8.62 (t, J=5.6 Hz, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 7.97 (s,1H), 7.77 (d, J=8.8 Hz, 1H), 7.47-7.35 (m, 6H), 6.88 (s, 1H), 6.84 (d,J=2.4 Hz, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 5.18 (d, J=2.4 Hz, 1H), 4.56(d, J=9.6 Hz, 1H), 4.46-4.42 (m, 1H), 4.41-4.33 (m, 2H), 4.28-4.22 (m,1H), 3.96 (s, 2H), 3.87 (s, 2H), 3.75 (s, 3H), 3.69 (s, 3H), 3.65 (d,J=3.2 Hz, 2H), 3.59 (s, 2H), 3.55-3.49 (m, 11H), 3.03-2.96 (m, 1H), 2.82(s, 3H), 2.44 (s, 3H), 2.08 (s, 3H), 1.92-1.90 (m, 1H), 1.66-1.54 (m,1H), 0.94 (s, 9H); LC-MS (ESI⁺) m/z 1148.2 (M+H)⁺.

Example 193:3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamide,I-193

Step 1—Ethyl5-[[1-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-3-methylsulfanyl-1,2,4-triazine-6-carboxylate

A mixture of benzylN-[2-[2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]ethoxy]ethyl]carbamate(250 mg, 566 umol, synthesized via Steps 1-2 of Example 166) and ethyl5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylate (140 mg, 599umol, CAS #75824-03-2) in NMP (3 mL) was stirred at rt for 1 hour. Oncompletion, the residue was purified by reverse phase chromatography(0.1% FA) to afford the title compound (220 mg, 56% yield) as a yellowoil. LC-MS (ESI⁺) m/z 639.1 (M+H)⁺.

Step 2—BenzylN-[2-[2-[2-[2-[4-[(6-carbamoyl-3-methylsulfanyl-1,2,4-triazin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate

A mixture of ethyl5-[[1-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl

]amino]-3-methylsulfanyl-1,2,4-triazine-6-carboxylate (220 mg, 344 umol)in MeOH (15 mL) and 70 N NH₃ in MeOH (15 mL) was stirred at −40° C. for1 hour. On completion, the mixture was concentrated in vacuo at 45° C.to afford the title compound (180 mg, 81% yield) as a yellow solid.LC-MS (ESI⁺) m/z 610.2 (M+H)⁺.

Step 3—Tert-ButylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-6-carbamoyl-1,2,4-triazin-3-yl]amino]cyclohexyl]carbamate

To a mixture of benzylN-[2-[2-[2-[2-[4-[(6-carbamoyl-3-methylsulfanyl-1,2,4-triazin-5-yl)amino]indol-1-yl]ethoxy]ethoxy]ethoxy]ethyl]carbamate(180 mg, 295 umol) in DMF (3 mL) was added m-CPBA (150 mg, 869 umol) inone portion at 0° C. under nitrogen. The mixture was stirred at rt for 1hour. On completion, TEA (255 mg, 2.52 mmol) and tert-butylN-[(1S,2R)-2-aminocyclohexyl]carbamate (100 mg, 466 umol) was added toabove solution. Then the reaction mixture was heated to 65° C. andstirred for 0.5 hour. On completion, the mixture was poured into water(50 mL) and stirred for 2 minutes. The aqueous phase was extracted withethyl acetate (3×50 mL). The combined organic phase was washed withbrine (1×50 mL), dried with anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by reverse phase chromatography (0.1%FA) to afford the title compound (120 mg, 49% yield) as yellow solid.LC-MS (ESI⁺) m/z 776.5 (M+H)⁺.

Step 4—Tert-ButylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]indol-4-yl]amino]-6-carbamoyl-1,2,4-triazin-3-yl]amino]cyclohexyl]

To a mixture of tert-butylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-6-carbamoyl-1,2,4-triazin-3-yl]amino]cyclohexyl]carbamate(120 mg, 154 umol) in EA (10 mL) was added Pd(OH)₂/C (270 mg, 10 wt %)and NH₃H₂O (100 uL) in one portion at rt under a hydrogen atmosphere (15psi pressure). The mixture was stirred at rt for 16 hours. LCMS showed30% starting material was not consumed. More Pd(OH)₂/C (150 mg, 10 wt %)was added to above solution, and the mixture was stirred at rt under ahydrogen atmosphere (15 psi pressure) for another 16 hours. Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo to afford the title compound (100 mg, 70% yield) as a yellowsolid. LC-MS (ESI⁺) m/z 642.3 (M+H)⁺.

Step 5—Tert-ButylN-[(1S,2R)-2-[[6-carbamoyl-5-[[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazin-3-yl]amino]cyclohexyl]carbamate

To a solution of tert-butylN-[(1S,2R)-2-[[5-[[1-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]indol-4-yl]amino]-6-carbamoyl-1,2,4-triazin-3-yl]amino]cyclohexyl]carbamate(82.0 mg, 128 umol) and2-(2,6-dioxo-3-piperidyl)-4-fluoroisoindoline-1,3-dione (38.8 mg, 141umol, Intermediate R) in DMF (3 mL) was added DIPEA (33.0 mg, 256 umol)under nitrogen atmosphere. The reaction mixture was stirred at 90° C.for 7 hours. On completion, the reaction mixture was concentrated invacuo. The residue was purified by prep-TLC (DCM:MeOH=10:1) to affordthe title compound (100 mg, 57% yield) as a yellow solid. LC-MS (ESI⁺)m/z 898.3 (M+H)⁺.

Step6-3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamide

To a solution of tert-butylN-[(1S,2R)-2-[[6-carbamoyl-5-[[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazin-3-yl]amino]cyclohexyl]carbamate(100 mg, 111 umol) in DCM (3 mL) was added HCl in dioxane (4N, 2 mL)under a nitrogen atmosphere. The reaction mixture was stirred at rt for2 hours. On completion, the reaction mixture was concentrated in vacuo.The residue was purified by prep-HPLC (column: Boston Green ODS 150*305u; mobile phase [water (0.225% FA)-ACN]; B %:24%-48%, 10 min) to affordthe title compound I-193 (10.0 mg, 11% yield). ¹H NMR (400 MHz, DMSO-d₆)δ 12.92 (s, 1H), 8.39 (d, J=12.8 Hz, 3H), 7.95-7.85 (m, 1H), 7.79-7.71(m, 1H), 7.69-7.52 (m, 1H), 7.45-7.32 (m, 1H), 7.31-7.21 (m, 1H),7.20-7.09 (m, 2H), 7.09-7.01 (m, 1H), 6.62-6.50 (m, 1H), 6.49-6.40 (m,1H), 5.10-5.01 (m, 1H), 4.45-4.32 (m, 2H), 3.95-3.82 (m, 1H), 3.80-3.60(m, 2H), 3.55-3.45 (m, 14H), 2.93-2.81 (m, 1H), 2.59-2.63 (m, 2H),2.06-1.95 (m, 1H), 1.89-1.72 (m, 2H), 1.68-1.49 (m, 4H), 1.45-1.25 (m,3H); LC-MS (ESI⁺) m/z 798.6 (M+H)⁺.

Example 194:3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamide,I-194

3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamidewas synthesized as described for Example 193, using benzylN-[2-[2-[2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(synthesized via Steps 1-2 of Example 167) as the starting material inthe first step. In Step 4, the hydrogenation was run at rt with 50 psipressure of hydrogen. In Step 6, TFA not HCl was used for the Bocdeprotection. The procedure was as follows:

A mixture of tert-butylN-[(1S,2R)-2-[[6-carbamoyl-5-[[1-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazin-3-yl]amino]cyclohexyl]carbamate(72 mg, 76.4 umol) in TFA (300 uL) and DCM (500 uL) was stirred at rtfor 0.5 hour. On completion, the mixture was concentrated in vacuo. Theresidue was purified by column (Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.05% HCCOH)-ACN]; B %: 10%-40%, 12 min) to affordthe title compound I-194 (20 mg, 30% yield) as a yellow solid. ¹H NMR(400 MHz, CD₃0D) δ 8.53 (br s, 1H), 7.45 (dd, J=7.2, 8.8 Hz, 1H), 7.33(d, J=3.2 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.21-7.12 (m, 1H), 7.00-6.95(m, 2H), 6.55 (d, J=3.2 Hz, 1H), 4.34 (t, J=4.8 Hz, 2H), 3.81 (t, J=5.2Hz, 2H), 3.63 (t, J=5.6 Hz, 2H), 3.60-3.55 (m, 4H), 3.55-3.49 (m, 6H),3.50-3.47 (m, 2H), 3.39 (t, J=5.2 Hz, 2H), 2.85-2.64 (m, 2H), 2.16-1.93(m, 2H), 1.90-1.75 (m, 5H), 1.73-1.47 (m, 3H), 1.41-1.25 (m, 2H). LC-MS(ESI⁺) m/z 842.5 (M+H)⁺.

Example 195:(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[[2-[4-[[7-[[(1R,2S)-2-Aminocyclohexylamino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide,I-195

Step 1—Ethyl 2-(4-nitroindol-1-yl)acetate

To a solution of 4-nitro-1H-indole (5.00 g, 30.8 mmol, CAS #4769-97-5)in DMF (100 mL) was added ethyl 2-bromoacetate (7.73 g, 46.3 mmol, 5.12mL), K₂CO₃ (12.8 g, 92.5 mmol) and NaI (462 mg, 3.08 mmol). The reactionmixture was stirred at 40° C. for 12 hrs. On completion, the reactionmixture was diluted with water (100 mL) and extracted withdichloromethane (3×200 mL). The combined organic layer was washed withbrine (200 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was triturated with ethyl acetate (30mL) to give the title compound (6.50 g, 85% yield) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.17 (dd, J=0.8, 8.2 Hz, 1H), 7.59 (d, J=8.2 Hz,1H), 7.38-7.36 (m, 1H), 7.35-7.29 (m, 2H), 4.94 (s, 2H), 4.24 (q, J=7.2Hz, 2H), 1.28 (t, J=7.2 Hz, 3H).

Step 2—Ethyl 2-(4-aminoindol-1-yl)acetate

To a solution of ethyl 2-(4-nitroindol-1-yl)acetate (2.60 g, 10.5 mmol)in THF (20 mL) was added Pd/C (260 mg, 10 wt %), and the suspension wasdegassed and purged with hydrogen gas three times. The mixture wasstirred under hydrogen (15 psi pressure) at rt for 12 hrs. Oncompletion, the reaction was filtered and concentrated in vacuo to givethe title compound (2.20 g, 96% yield) as a colorless oil. ¹H NMR (400MHz, CDCl₃) δ 7.06 (t, J=8.0 Hz, 1H), 7.02 (d, J=3.2 Hz, 1H), 6.72 (d,J=8.0 Hz, 1H), 6.49 (dd, J=0.8, 3.2 Hz, 1H), 6.43 (dd, J=0.8, 8.0 Hz,1H), 4.81 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).

Step 3—Ethyl2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetate

To a solution of ethyl 2-(4-aminoindol-1-yl)acetate (2.20 g, 10.1 mmol)in NMP (40 mL) was added 5,7-dichloro-3H-pyrido[4,3-d]pyrimidin-4-one(2.18 g, 10.1 mmol, Intermediate FB) under nitrogen. The reactionmixture was stirred at 140° C. for 1 hr. On completion, the reactionmixture was concentrated in vacuo. The residue was triturated withDMF/MeOH=(5 mL/10 mL) to give the title compound (3.20 g, 80% yield) asa yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (s, 1H), 11.76 (s, 1H),8.32 (s, 1H), 8.22-8.15 (m, 1H), 7.41 (d, J=3.2 Hz, 1H), 7.21-7.15 (m,2H), 6.92 (s, 1H), 6.60 (d, J=3.2 Hz, 1H), 5.16 (s, 2H), 4.16 (q, J=7.2Hz, 2H), 1.22 (t, J=7.2 Hz, 3H).

Step4-2-[4-[(7-Chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]aceticAcid

To a solution of ethyl 2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetate (2.00 g, 5.03 mmol) inTHF (30 mL) and H₂O (10 mL) was added LiOH—H₂O (633 mg, 15.0 mmol). Thereaction mixture was stirred at rt for 12 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was acidifiedwith HCl (2 N, 20 mL) to pH=3. The precipitate was collected byfiltration and the solid was dried in vacuo to give the title compound(1.80 g, 87% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.98(s, 2H), 11.78 (s, 1H), 8.31 (s, 1H), 8.22-8.13 (m, 1H), 7.41 (d, J=3.2Hz, 1H), 7.22-7.13 (m, 2H), 6.91 (s, 1H), 6.59 (d, J=3.2 Hz, 1H), 5.04(s, 2H); LC-MS (ESI⁺) m/z 370.0 (M+H)⁺.

Step 5—Ethyl2-[2-[2-[2-[2-[[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetate (287 mg, 1.03mmol, Intermediate DW) and2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]aceticacid (380 mg, 1.03 mmol) in DMF (10 mL) was added DIPEA (398 mg, 3.08mmol). After stirring for 30 minutes, HATU (430 mg, 1.13 mmol) wasadded. The mixture was stirred at rt for 2 hours. On completion, 50 mLwater was added to the mixture. A large quantity of yellow precipitateformed, which was collected by filtration to give the title compound(575 mg, 88% yield) as a yellow solid. LC-MS (ESI⁺) m/z 631.2 (M+H)⁺.

Step6-2-[2-[2-[2-[2-[[2-[4-[(7-Chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a mixture of ethyl2-[2-[2-[2-[2-[[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetate (600 mg, 950umol) in THF (10 mL) and H₂O (10 mL), was added LiOH (228 mg, 9.51mmol). Then, the mixture was stirred at rt for 5 hours. On completion,the mixture was adjusted to pH=5 with HCl (1N), then the mixture wasextracted with DCM (2×20 mL). The combined organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (400 mg, 69% yield) as a yellow solid. LC-MS (ESI⁺) m/z 603.1(M+H)⁺.

Step7—(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[[2-[4-[(7-Chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

A mixture of2-[2-[2-[2-[2-[[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (400 mg, 597 umol),(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(279 mg, 597 umol, HCl salt, Intermediate CI), and DIPEA (308 mg, 2.39mmol) in DMF (20 mL) was degassed and purged with nitrogen gas threetimes. Then HATU (249 mg, 657 umol) was added, and the mixture wasstirred at rt for 2 hours under a nitrogen atmosphere. On completion,the mixture was poured into water (50 mL) and extracted with DCM (2×40mL). The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified bysilica column chromatography to give the title compound (110 mg, 18%yield) as a yellow solid. LC-MS (ESI⁺) m/z 1037.6 (M+Na)⁺.

Step8—(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[[2-[4-[[7-[[(1R,2S)-2-Aminocyclohexylamino]-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl]amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

A mixture of(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[[2-[4-[(7-chloro-4-oxo-3H-pyrido[4,3-d]pyrimidin-5-yl)amino]indol-1-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(60.0 mg, 59.0 umol) and (1R,2S)-cyclohexane-1,2-diamine (67.4 mg, 590umol) in NMP (0.5 mL) was heated under microwave irradiation at 150° C.for 1.5 hours. On completion, the mixture was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]) to give the title compound I-195 (26.0 mg, 40% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 9.06-8.91(m, 1H), 8.62 (t, J=6.0 Hz, 1H), 8.39-8.32 (m, 2H), 7.93 (s, 1H),7.49-7.29 (m, 6H), 7.14-6.99 (m, 2H), 6.58 (d, J=3.2 Hz, 1H), 6.03 (s,1H), 4.83 (s, 2H), 4.57 (d, J=9.6 Hz, 1H), 4.49-4.33 (m, 3H), 4.25 (m,2H), 3.97 (s, 2H), 3.71-3.40 (m, 17H), 3.25 (m, 2H), 2.57-2.52 (m, 4H),2.45 (s, 3H), 2.12-2.01 (m, 1H), 1.96-1.78 (m, 3H), 1.65 (d, J=11.2 Hz,4H), 1.41 (s, 2H), 1.00-0.88 (m, 9H); LC-MS (ESI⁺) m/z 1093.2 (M+H)⁺.

Example 196:3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[[(1S)-1-(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamide,I-196

Step 1-2-[2-[2-[2-(4-Nitroindol-1-yl)ethoxy]ethoxy]ethoxy]acetic Acid

To a mixture of ethyl2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]acetate (1.10 g, 3.51mmol, Intermediate BI) and 4-nitro-1H-indole (500 mg, 3.08 mmol) in DMF(10 mL) was added Cs₂CO₃ (2.51 g, 7.70 mmol) in one portion at rt undernitrogen. The mixture was stirred at 100° C. for 16 hours. Next,LiOH·H₂O (129 mg, 3.08 mmol) in MeOH (3 mL) was then added to abovesolution, and the solution was stirred at rt for 4 hours. On completion,the mixture was poured into water (50 mL) and stirred for 2 minutes. Theaqueous phase was extracted with ethyl acetate (4×50 mL). The combinedorganic phase was washed with H₂O (2×20 mL), the combined aqueous phasewas adjusted to pH=5 with citric acid. The aqueous phase was thenextracted with ethyl acetate (4×50 mL). The combined organic phase waswashed with brine (2×50 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound (1.00 g, 92% yield)as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=8.0 Hz, 1H), 7.75(d, J=8.0 Hz, 1H), 7.47 (d, J=3.2 Hz, 1H), 7.31-7.28 (m, 1H), 7.27-7.23(m, 1H), 4.41 (t, J=5.6 Hz, 2H), 4.15 (s, 2H), 3.84 (t, J=5.6 Hz, 2H),3.72-3.64 (m, 2H), 3.63-3.47 (m, 6H).

Step2—(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a mixture of2-[2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]ethoxy]acetic acid (171 mg,484 umol) and(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (200 mg, 428 umol, HCl, IntermediateCI) in DMF (2 mL) was added TEA (183 mg, 1.80 mmol) and HATU (299 mg,787 umol) in one portion at rt. The mixture was stirred at rt for 3hours. On completion, the mixture was poured into water (30 mL) andstirred for 2 minutes. The aqueous phase was extracted with ethylacetate (3×30 mL). The combined organic phase was washed with brine(1×20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the title compound (270 mg, 82% yield) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 8.14 (d, J=7.2 Hz, 1H),7.69 (d, J=8.0 Hz, 1H), 7.45 (d, J=3.2 Hz, 1H), 7.34 (q, J=8.4 Hz, 5H),7.24 (d, J=4.0 Hz, 2H), 4.73 (t, J=8.0 Hz, 1H), 4.59-4.51 (m, 2H), 4.48(d, J=8.4 Hz, 1H), 4.41-4.29 (m, 3H), 4.18-4.11 (m, 1H), 4.05-3.94 (m,2H), 3.81 (t, J=5.2 Hz, 2H), 3.77-3.68 (m, 1H), 3.63-3.53 (m, 8H), 2.82(br s, 1H), 2.63-2.55 (m, 1H), 2.52 (s, 3H), 2.12 (dd, J=8.0, 13.6 Hz,1H), 0.94 (s, 9H).

Step3—(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a mixture of(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-(4-nitroindol-1-yl)ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(270 mg, 353 umol) in EA (10 mL) was added Pd/C (100 mg, 10 wt %) in oneportion at rt under hydrogen (15 psi pressure). The mixture was stirredat rt for 16 hours. On completion, the mixture was filtered andconcentrated in vacuo to afford the title compound (200 mg, 77.1% yield)as a yellow solid. LC-MS (ESI⁺) m/z 757.1 (M+Na)⁺.

Step 4—Ethyl5-[[1-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-3-methylsulfanyl-1,2,4-triazine-6-carboxylate

A mixture of(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(4-aminoindol-1-yl)ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(200 mg, 272 umol) and ethyl5-chloro-3-methylsulfanyl-1,2,4-triazine-6-carboxylate (64.8 mg, 278umol) in NMP (2 mL) was stirred at rt for 1 hour. On completion, themixture was purified by reverse phase flash column (0.1% FA) to affordthe title compound (200 mg, 79% yield) as a blue oil. LC-MS (ESI⁺) m/z932.7 (M+H)⁺.

Step5-5-[[1-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-3-methylsulfanyl-1,2,4-triazine-6-carboxamide

To a mixture of ethyl5-[[1-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-3-methylsulfanyl-1,2,4-triazine-6-carboxylate(200 mg, 215 umol) in MeOH (300 uL) was added 17 N NH₃ in MeOH (300 uL)in one portion at −40° C. under nitrogen. The mixture was stirred at−40° C. for 1 hour. On completion, the mixture was concentrated atreduced pressure at 45° C. The residue was purified by reverse phaseflash column (0.1% FA) to afford the title compound (160 mg, 78% yield)as a yellow solid. LC-MS (ESI⁺) m/z 903.4 (M+H)⁺.

Step6-3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamide

5-[[1-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-3-methylsulfanyl-1,2,4-triazine-6-carboxamide(150 mg, 166 umol) and (1R,2S)-cyclohexane-1,2-diamine (200 mg, 1.75mmol) dissolved in a microwave tube in NMP (3 mL). The sealed tube washeated at 150° C. for 1.5 hours under microwave. On completion, theresidue was purified by column (Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.05% HCl)-ACN]; B %: 10%-40%, 12 min) to affordthe title compound I-196 (107 mg, 60% yield) as a red solid. ¹H NMR (400MHz, DMSO-d₆) δ 12.91 (s, 1H), 9.24 (d, J=7.2 Hz, 1H), 9.15-9.08 (m,1H), 8.90-8.70 (m, 1H), 8.70-8.60 (m, 1H), 8.49-8.39 (m, 1H), 8.44-8.34(m, 2H), 7.94 (d, J=7.6 Hz, 1H), 7.51-7.37 (m, 7H), 7.27-7.18 (m, 1H),6.52 (d, J=2.4 Hz, 1H), 4.55 (d, J=10.8 Hz, 1H), 4.44 (t, J=8.2 Hz, 2H),4.40-4.34 (m, 5H), 4.30-4.24 (m, 1H), 4.20-1.12 (m, 1H), 3.73 (d, J=4.8Hz, 2H), 3.66-3.60 (m, 2H), 3.59-3.47 (m, 12H), 2.43 (s, 3H), 2.11-2.03(m, 1H), 1.93-1.80 (m, 4H), 1.70-1.60 (m, 3H), 1.45-1.30 (m, 2H), 0.93(s, 9H); LC-MS (ESI⁺) m/z 969.5 (M+H)⁺.

Example 197:3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamide,I-197

3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-[[1-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]indol-4-yl]amino]-1,2,4-triazine-6-carboxamideI-197 was synthesized as described for Example 196, using IntermediateBK as the mesylate in the first step. Characterization of the finalcompound: ¹H NMR (400 MHz, DMSO-d₆) δ 12.93 (s, 1H), 9.26 (d, J=8.0 Hz,1H), 9.21-9.17 (m, 1H), 8.77-8.65 (m, 1H), 8.67 (t, J=5.6 Hz, 1H), 8.45(br s, 1H), 8.36 (br s, 2H), 7.94 (d, J=7.6 Hz, 1H), 7.52-7.42 (m, 4H),7.40 (s, 5H), 7.37-7.27 (m, 1H), 6.52 (d, J=2.8 Hz, 1H), 4.55 (d, J=9.6Hz, 1H), 4.46-4.38 (m, 2H), 3.95 (s, 2H), 3.73 (d, J=5.2 Hz, 2H),3.71-3.65 (m, 1H), 3.68-3.26 (m, 20H), 2.46-2.40 (m, 3H), 2.10-2.03 (m,1H), 1.95-1.75 (m, 5H), 1.68-1.58 (m, 4H), 1.45-1.25 (m, 2H), 0.92 (s,9H); LC-MS (ESI⁺) m/z 1013.3 (M+H)⁺.

Example 198:5-[[(1S,2R)-2-aminocyclohexyl]amino-7-[3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidine-8-carboxamide,I-198

Step 1—Benzyl(2-(2-(2-(2-(3-((8-carbamoyl-5-(methylthio)imidazo[1,2-c]pyrimidin-7-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

To a solution of7-(3-hydroxy-5-methoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(300 mg, 869 umol, Intermediate EZ) in DMF (10 mL) was added K₂CO₃ (480mg, 3.47 mmol) and2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (1.76 g, 4.34 mmol, Intermediate EY) under nitrogenatmosphere. The reaction mixture was stirred at 100° C. for 12 hrs. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas extracted with ethyl acetate (100 mL) and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by reverse phasechromatography (0.1% NH₃H₂O) to give the title compound (380 mg, 67%yield) as a yellow oil. LC-MS (ESI⁺) m/z 655.1 (M+H)⁺.

Step 2—Benzyl(2-(2-(2-(2-(3-((5-(((1S,2R)-2-aminocyclohexyl)amino)-8-carbamoylimidazo[1,2-c]pyrimidin-7-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

A solution of benzylN-[2-[2-[2-[2-[3-[(8-carbamoyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidin-7-yl)-amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(200 mg, 305 umol) and (1R,2S)-cyclohexane-1,2-diamine (38.4 mg, 336umol) in DMF (5 mL) was heated to 90° C. for 12 hrs. On completion, thereaction mixture was concentrated in vacuo to give the title compound(220 mg, 100% yield) as a yellow oil. LC-MS (ESI⁺) m/z 721.1 (M+H)⁺.

Step 3—Tert-ButylN-[(1R,2S)-2-[[7-[3-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxyl-5-methoxy-anilino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbmate

To a solution of benzylN-[2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-aminocyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(220 mg, 305 umol) in methanol (3 mL) was added 12 (7.75 mg, 30.5 umol)and (Boc)₂O (133 mg, 610 umol) at rt. The reaction mixture was stirredat rt for 6 hrs. On completion, the reaction mixture was concentrated invacuo. The residue was purified by silica gel chromatography(dichloromethane:methanol=20:1) to give the title compound (230 mg, 91%yield) as a yellow oil. LC-MS (ESI⁺) m/z 821.1 (M+H)⁺.

Step 4—Tert-ButylN-[(1R,2S)-2-[[7-[3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbamate

To a solution of tert-butylN-[(1R,2S)-2-[[7-[3-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbamate(230 mg, 280 umol) in ethyl acetate (3 mL) was added Pd(OH)₂/C (120 mg,280 umol, 10 wt %) under nitrogen atmosphere. The suspension wasdegassed and purged with hydrogen three times. The mixture was stirredunder hydrogen gas (15 psi pressure) at rt for 12 h. On completion, thereaction mixture was filtered and the filtrate was concentrated in vacuoto give the title compound (130 mg, 65% yield) as yellow oil. LC-MS(ESI⁺) m/z 687.2 (M+H)⁺.

Step 5—Tert-ButylN-[(1R,2S)-2-[[8-carbamoyl-7-[3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbamate

To a solution of tert-butylN-[(1R,2S)-2-[[7-[3-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbamate(130 mg, 189 umol) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (57.5 mg, 208umol, Intermediate R) in DMF (4 mL) was added DIPEA (73.4 mg, 568 umol)under nitrogen. The reaction mixture was stirred at 90° C. for 12 h. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by reverse phase chromatography to give the title compound(70.0 mg, 39% yield) as a yellow solid. LC-MS (ESI⁺) m/z 943.1 (M+H)⁺.

Step6-5-[[(1S,2R)-2-aminocyclohexyl]amino]-7-[3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidine-8-carboxamide

To a solution of tert-butylN-[(1R,2S)-2-[[8-carbamoyl-7-[3-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-5-methoxy-anilino]imidazo[1,2-c]pyrimidin-5-yl]amino]cyclohexyl]carbamate(70.0 mg, 74.2 umol) in DCM (4 mL) was added HCl in dioxane (4 M, 4.00mL) at rt. The reaction mixture was stirred at rt for 1 hour. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (column: Boston pH-lex 150*25 10 um; mobilephase: [water (0.225% FA)-ACN]; B %: 20%-50%) to give the title compoundI-198 (13.5 mg, 21% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ12.39 (s, 1H), 9.55 (d, J=3.2 Hz, 1H), 8.36 (s, 1H), 8.12 (s, 1H),7.57-7.53 (m, 1H), 7.40 (d, J=3.6 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.10(d, J=8.4 Hz, 1H), 7.01 (d, J=6.8 Hz, 1H), 6.93 (s, 1H), 6.67 (s, 1H),6.58 (t, J=5.6 Hz, 1H), 6.20 (s, 1H), 5.06-5.02 (m, 1H), 4.20 (d, J=11.2Hz, 1H), 4.08-4.04 (m, 2H), 3.74 (s, 3H), 3.71 (s, 2H), 3.62 (s, 2H),3.59-3.50 (m, 12H), 2.92-2.81 (m, 1H), 2.62-2.58 (m, 2H), 2.28-2.26 (m,1H), 2.04-1.94 (m, 2H), 1.82-1.64 (m, 4H), 1.56-1.53 (m, 2H), 1.46-1.33(m, 2H); LC-MS (ESI⁺) m/z 843.4 (M+H)⁺.

Example 199: Tert-Butyl((1R,2S)-2-((8-carbamoyl-7-((3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)-5-methoxyphenyl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)cyclohexyl)carbamate,I-199

Tert-butyl((1R,2S)-2-((8-carbamoyl-7-((3-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxatetradecyl)oxy)-5-methoxyphenyl)amino)imidazo[1,2-c]pyrimidin-5-yl)amino)cyclohexyl)carbamateI-199 was synthesized as described above for Example 198 usingIntermediate FC as the mesylate. Step 1 was run at 60 C for 12 h.Characterization of the final product: ¹H NMR (400 MHz, DMSO-d₆) δ 12.39(s, 1H), 9.55 (s, 1H), 8.36 (s, 2H), 8.13 (s, 1H), 7.58-7.53 (m, 1H),7.39 (s, 1H), 7.32 (s, 1H), 7.11 (d, J=8.4 Hz, 1H), 7.02 (d, J=6.8 Hz,1H), 6.93 (s, 1H), 6.67 (s, 1H), 6.58 (s, 1H), 6.21 (s, 1H), 5.04 (dd,J=5.2, 13.2 Hz, 1H), 4.22 (d, J=10.4 Hz, 1H), 4.07 (s, 2H), 3.74 (s,3H), 3.71 (s, 2H), 3.64-3.56 (m, 18H), 2.89-2.85 (m, 2H), 2.63-2.60 (m,2H), 2.27-2.65 (m, 1H), 1.80-1.72 (m, 1H), 1.71-1.65 (m, 4H), 1.56-1.52(m, 2H), 1.45-1.51 (m, 2H); LC-MS (ESI⁺) m/z 887.4 (M+H)⁺.

Example 200:5-(((1S,2R)-2-aminocyclohexyl)amino)-7-((4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,5-dimethoxyphenyl)amino)imidazo[1,2-c]pyrimidine-8-carboxamide,I-200

Step 1—Benzyl(2-(2-(2-(2-(4-((8-carbamoyl-5-(methylthio)imidazo[1,2-c]pyrimidin-7-yl)amino)-2,6-dimethoxyphenoxy)ethoxy)ethoxy)ethoxy)ethyl)carbamate

To a mixture of7-(4-hydroxy-3,5-dimethoxy-anilino)-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(200 mg, 532 umol, Intermediate FA) in DMF (3 mL) was added2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethylmethanesulfonate (237 mg, 586 umol,Intermediate EY) and K₂CO₃ (220 mg, 1.60 mmol). Then the reactionmixture was stirred at 70° C. for 12 hours. On completion, the reactionmixture was washed with water (50 mL) and extracted with ethyl acetate(2×50 mL). The combined organic layer was dried with Na₂SO₄, filtratedand concentrated in vacuo. The residue was purified by prep-columnchromatography (PE:EA=3:1 to DCM:MeOH=20:1) to give the title compound(172 mg, 47% yield) as a yellow oil. LC-MS (ESI⁺) m/z 685.0 (M+H)⁺.

Step2-7-((4-(2-(2-(2-(2-Aminoethoxy)ethoxy)ethoxy)ethoxy)-3,5-dimethoxyphenyl)amino)-5-(methylthio)imidazo[1,2-c]pyrimidine-8-carboxamide

To a mixture of benzylN-[2-[2-[2-[2-[4-[(8-carbamoyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidin-7-yl)amino]-2,6-dimethoxyphenoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate(200 mg, 292 umol) in CH₃CN (2 mL) was added HBr in HOAc (32.9 mg, 292umol, 1 mL). Then the reaction mixture was stirred at 50° C. for 1 hour.On completion, the reaction mixture was quenched with sat. NaHCO₃ (3×30mL) and extracted with DCM (3×30 mL). The organic layer was dried withNa₂SO₄, filtrated and concentrated in vacuo. The residue was purified byreverse phase chromatography (0.1% FA in water) to give the titlecompound (70.0 mg, 43% yield) as a yellowish oil.

Step3-7-((4-(2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,5-dimethoxyphenyl)amino)-5-(methylthio)imidazo[1,2-c]pyrimidine-8-carboxamide

To a mixture of7-[4-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-3,5-dimethoxy-anilino]-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(70.0 mg, 127 umol) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (38.6 mg, 139umol, Intermediate R) in DMF (1.5 mL) was added DIPEA (32.8 mg, 254umol). Then the reaction mixture was stirred at 90° C. for 8 hours. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-TLC (PE:EA=0:1) to give the title compound (30.0mg, 23% yield) as a yellowish solid. LC-MS (ESI⁺) m/z 829.1 (M+Na)⁺.

Step4-5-(((1S,2R)-2-aminocyclohexyl)amino)-7-((4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)ethoxy)-3,5-dimethoxyphenyl)amino)imidazo[1,2-c]pyrimidine-8-carboxamide

To a mixture of7-[4-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]-3,5-dimethoxy-anilino]-5-methylsulfanyl-imidazo[1,2-c]pyrimidine-8-carboxamide(30.0 mg, 37.1 umol) in DMF (1 mL) was added(1R,2S)-cyclohexane-1,2-diamine (8.49 mg, 74.3 umol). Then the reactionmixture was stirred at 90° C. for 8 hours. On completion, the reactionmixture was concentrated in vacuo. The residue was purified by prep-HPLC(column: Boston Green ODS 150*30 5u; mobile phase: [water (0.225%FA)-ACN]; B %: 20%-44%, 10 min) to give the title compound I-200 (6.00mg, 18% yield) as a yellowish oil. ¹H NMR (400 MHz, DMSO-d₆) δ 12.19 (s,1H), 9.53 (d, J=2.8 Hz, 1H), 8.36 (s, 1H), 8.12 (s, 1H), 7.57 (t, J=7.6Hz, 1H), 7.37 (d, J=3.2 Hz, 1H), 7.32 (s, 1H), 7.14 (d, J=8.4 Hz, 1H),7.03 (d, J=7.2 Hz, 1H), 6.91-6.76 (m, 2H), 6.61 (t, J=5.6 Hz, 1H), 5.05(dd, J=5.6, 12.0 Hz, 1H), 4.19 (d, J=10.4 Hz, 1H), 4.12-4.06 (m, 1H),4.05-3.99 (m, 1H), 3.93 (d, J=4.8 Hz, 1H), 3.79 (s, 6H), 3.64-3.63 (m,4H), 3.56-3.50 (m, 8H), 2.94-2.88 (m, 2H), 2.08-1.85 (m, 3H), 1.76-1.19(m, 9H); LC-MS (ESI⁺) m/z 873.1 (M+H)⁺.

Example 201: ()-2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-[2-[5-[[4-[6-(3-ethylpiperazin-1-yl)-3-pyridyl]pyrimidin-2-yl]amino]-2,3-dimethoxyphenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione,I-201

Step 1—BenzylN-[2-[2-[2-[2-[2-(2,3-dimethoxy-5-nitro-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a mixture of2-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethylmethane sulfonate (606 mg, 1.35 mmol, Intermediate FC) in DMF (10 mL)was added 2,3-dimethoxy-5-nitro-phenol (268 mg, 1.35 mmol, IntermediateFG) and potassium carbonate (559 mg, 4.05 mmol). Then the reactionmixture was stirred at 70° C. for 12 hours. On completion, the reactionmixture was washed with water (20 mL) and extracted with ethyl acetate(3×30 mL). The combined organic layer was dried with anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn (petroleum ether:ethyl acetate=1:1 todichloromethane:methanol=20:1) to give the title compound (610 mg, 74%yield) as a yellowish oil. LC-MS (ESI⁺) m/z 553.1 (M+H)⁺.

Step 2—BenzylN-[2-[2-[2-[2-[2-(5-amino-2,3-dimethoxy-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of benzylN-[2-[2-[2-[2-[2-(2,3-dimethoxy-5-nitro-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (460 mg, 832 umol) in water (2 mL) and ethanol (8mL) was added ammonium chloride (445 mg, 8.32 mmol) and Fe (464 mg, 8.32mmol). The reaction mixture was stirred at 78° C. for 1 hour. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was purified by silica gel chromatography(dichloromethane:methanaol=50:1) to give the title compound (430 mg, 98%yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.35 (m, 5H),6.03-5.82 (m, 2H), 5.52 (br s, 1H), 5.16-5.07 (m, 2H), 4.19-4.08 (m,2H), 3.84 (d, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.77 (s, 3H), 3.74-3.70 (m,2H), 3.68-3.63 (m, 10H), 3.59-3.55 (m, 3H), 3.44-3.39 (m, 2H); LC-MS(ESI⁺) m/z 523.1 (M+H)⁺.

Step 3—(±)-Tert-butyl4-[5-[2-[3-[2-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxyanilino]pyrimidin-4-yl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate

To a solution of (±)-tert-butyl2-ethyl-4-[5-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate(200 mg, 446 umol, Intermediate FH) and benzylN-[2-[2-[2-[2-[2-(5-amino-2,3-dimethoxyphenoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (233 mg, 446 umol) in toluene (3mL) was added Pd(OAc)₂ (10.0 mg, 44.6 umol), BINAP (41.7 mg, 67.0 umol),cesium carbonate (436 mg, 1.34 mmol) and 4A MS (1.00 g, 446 umol) undernitrogen. The reaction mixture was stirred at 100° C. for 12 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was purified by reverse phase chromatography (0.1% FA inwater) to give the title compound (160 mg, 32% yield) as a yellow oil.¹H NMR (400 MHz, CDCl₃) δ 8.87 (d, J=2.4 Hz, 1H), 8.34 (d, J=5.2 Hz,1H), 8.20 (dd, J=2.4, 9.2 Hz, 1H), 7.37-7.29 (m, 5H), 7.19 (d, J=2.0 Hz,1H), 7.03 (d, J=5.2 Hz, 1H), 6.92 (s, 1H), 6.65 (d, J=9.2 Hz, 1H), 5.59(br s, 1H), 5.09 (s, 2H), 4.36-4.24 (m, 2H), 4.20 (t, J=4.8 Hz, 2H),4.16-3.97 (m, 2H), 3.91 (s, 3H), 3.87 (t, J=4.8 Hz, 2H), 3.84 (s, 3H),3.72 (d, J=4.8 Hz, 2H), 3.63-3.61 (m, 10H), 3.57-3.53 (m, 2H), 3.42-3.36(m, 2H), 3.24 (dd, J=4.0, 13.2 Hz, 1H), 3.18-3.01 (m, 2H), 1.66-1.56 (m,2H), 1.50 (s, 9H), 0.92 (t, J=7.2 Hz, 3H).

Step 4—(±)-Tert-Butyl4-[5-[2-[3-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy-anilino]pyrimidin-4-yl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate

To a mixture of (±)-tert-butyl4-[5-[2-[3-[2-[2-[2-[2-[2-(benzyloxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy-anilino]pyrimidin-4-yl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate(160 mg, 179 umol) in NH₃—H₂O (50 uL) and methanol (6 mL) was addedPd(OH)₂/C (60.0 mg, 10 wt %). Then the reaction mixture was stirred atrt for 10 hours under hydrogen (50 psi pressure). On completion, thereaction mixture was concentrated in vacuo to give the title compound(130 mg, 95% yield) as a yellowish oil. LC-MS (ESI⁺) m/z 756.4 (M+H)⁺.

Step 5—(±)-Tert-Butyl4-[5-[2-[3-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy-anilino]pyrimidin-4-yl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate

To a mixture of (±)-tert-butyl4-[5-[2-[3-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxyanilino]pyrimidin-4-yl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate(70.0 mg, 92.6 umol) in DMF (2 mL) was added(±)-2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (28.1 mg,101 umol, Intermediate R) and DIPEA (29.9 mg, 231 umol, 40.4 uL). Thenthe reaction mixture was stirred at 90° C. for 12 hours. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby prep-TLC (dichloromethane:methanaol=20:1) to give the title compound(40.0 mg, 40% yield) as a yellowish solid. LC-MS (ESI⁺) m/z 1012.2(M+H)⁺.

Step6—(±)-2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-[2-[5-[[4-[6-(3-ethylpiperazin-1-yl)-3-pyridyl]pyrimidin-2-yl]amino]-2,3-dimethoxyphenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a mixture of (±)-tert-butyl4-[5-[2-[3-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy-anilino]pyrimidin-4-yl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate(73.0 mg, 72.1 umol) in a mixture of methanol (1 mL) and dichloromethane(1 mL) was added 4M HCl in dioxane (72.1 umol, 1.00 mL) at 0° C. Thenthe reaction mixture was allowed to warm to rt and stirred for 2 hours.On completion, the reaction mixture was concentrated in vacuo. Theresidue was purified by prep-HPLC (column: Boston Green ODS 150*30 5u;mobile phase: [water (0.225% FA)-ACN]; B %: 27%-48%, 10 min) to give thetitle compound I-201 (35.0 mg, 53% yield) as a yellowish solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 9.39 (s, 1H), 8.93 (s, 1H), 8.42 (d,J=5.6 Hz, 1H), 8.26 (d, J=9.2 Hz, 1H), 7.56 (t, J=7.6 Hz, 1H), 7.34-7.22(m, 3H), 7.16-7.09 (m, 1H), 7.06-6.99 (m, 1H), 6.98-6.88 (m, 1H),6.67-6.54 (m, 1H), 6.58 (t, J=5.6 Hz, 1H), 5.05 (dd, J=5.2, 13.2 Hz,1H), 4.39-4.19 (m, 2H), 4.11 (d, J=3.6 Hz, 2H), 3.79 (s, 3H), 3.65 (s,3H), 3.63-3.57 (m, 6H), 3.56-3.52 (m, 2H), 3.54-3.50 (m, 6H), 3.47-3.41(m, 4H), 3.00 (d, J=11.6 Hz, 2H), 2.86 (d, J=12.0 Hz, 3H), 2.75-2.64 (m,3H), 2.10-1.95 (m, 1H), 1.50-1.34 (m, 2H), 0.95 (t, J=7.6 Hz, 3H); LC-MS(ESI⁺) m/z 912.2 (M+H)⁺.

Example 202:(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[5-[[4-[6-(3-ethylpiperazin-1-yl)-3-pyridyl]pyrimidin-2-yl]amino]-2,3-dimethoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide,I-202

Step1—Ethyl2-[2-[2-[2-[2-[2-[3-[(8-carbamoyl-5-methylsulfanyl-imidazo[1,2-c]pyrimidin-7-yl)amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of 2,3-dimethoxy-5-nitro-phenol (510 mg, 2.56 mmol,Intermediate FG) and ethyl 2-[2-[2-[2-(2-methylsulfonyloxyethoxy)ethoxy]ethoxy]ethoxy]acetate (1.10 g, 3.07 mmol,Intermediate BK) in DMF (15 mL) was added K₂CO₃ (1.06 g, 7.68 mmol). Themixture was stirred at 50° C. for 12 hours. On completion, the reactionmixture was diluted with water (20 mL) and extracted with DCM (3×30 mL).The combined organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo to give a residue. The residue was purified bycolumn chromatography (PE:EA=1:1) to give the title compound (1.10 g,93% yield) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d,J=2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 4.26-4.16 (m, 4H), 4.13 (s, 2H),3.95 (s, 3H), 3.92 (s, 3H), 3.90 (m, 2H), 3.74-3.63 (m, 12H), 1.27 (t,J=14.4 Hz, 3H); LC-MS (ESI⁺) m/z 431.1 (M+18)⁺.

Step 2—Ethyl2-[2-[2-[2-[2-(5-amino-2,3-dimethoxy-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-[2-(2,3-dimethoxy-5-nitro-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (600 mg, 1.30 mmol) in MeOH (8 mL) was added Pd/C (300 mg, 10 wt%) under nitrogen atmosphere. The suspension was degassed and purgedwith hydrogen gas three times. The mixture was stirred under hydrogen(15 psi pressure) at rt for 12 hours. On completion, the reactionmixture was filtered and concentrated in vacuo to give the titlecompound (400 mg, 71% yield) as a red oil. ¹H NMR (400 MHz, CDCl₃) δ5.97 (s, 1H), 5.94 (s, 1H), 4.26-4.18 (m, 1H), 4.22 (q, J=7.2 Hz, 1H),4.16-4.09 (m, 4H), 3.87-3.83 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H),3.74-3.65 (m, 12H), 1.31-1.27 (t, J=7.2 Hz, 3H); LC-MS (ESI⁺) m/z 432.1(M+H)⁺.

Step3—Ethyl-2-[2-[2-[2-[2-[2-[3-[[5-[[(1S,2R)-2-(tert-butoxycarbonylamino)cyclohexyl]amino]-8-carbamoyl-imidazo[1,2-c]pyrimidin-7-yl]amino]-5-methoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetate

To a solution of ethyl2-[2-[2-[2-[2-(5-amino-2,3-dimethoxy-phenoxy)ethoxy]ethoxy]ethoxy]ethoxy]acetate (300 mg, 695 umol) and tert-butyl2-ethyl-4-[5-(2-methylsulfonylpyrimidin-4-yl)-2-pyridyl]piperazine-1-carboxylate(311 mg, 695 umol, Intermediate FH) in toluene (10 mL) was added 4A MS(600 mg), Cs₂CO₃ (679 mg, 2.09 mmol), BINAP (64.9 mg, 104 umol) andPd(OAc)₂ (15.6 mg, 69.5 umol) under nitrogen atmosphere. The suspensionwas degassed and purged with nitrogen three times. The mixture wasstirred at rt for 1 h, and then heated to 100° C. for 12 hours. Oncompletion, the reaction mixture was concentrated under reduced pressureto remove the toluene. The residue was diluted with water (5 mL) andextracted with DCM (3×6 mL). The combined organic layers were dried oversodium sulfate, filtered and concentrated in vacuo to give a residue.The residue was purified by reverse phase chromatography (0.1% FA inwater) to give the title compound (400 mg, 72% yield) as a yellowishsolid. LC-MS (ESI⁺) m/z 799.2 (M+H)⁺.

Step4-2-[2-[2-[2-[2-[5-[[4-[6-(4-tert-butoxycarbonyl-3-ethyl-piperazin-1-yl)-3-pyridyl]pyrimidin-2-yl]amino]-2,3-dimethoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticacid

To a solution of tert-butyl4-[5-[2-[3-[2-[2-[2-[2-(2-ethoxy-2-oxo-ethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy-anilino]pyrimidin-4-yl]-2-pyridyl]-2-ethyl-piperazine-1-carboxylate(200 mg, 250 umol) in THF (6 mL) was added a solution of LiOH (52.5 mg,1.25 mmol) in H₂O (1 mL). The reaction mixture was stirred at rt for 3hours. On completion, the mixture saturated citric acid aqueous solution(0.3 mL) was added to the mixture to adjust the pH to 5. The residue wasdiluted with 3 mL water and extracted with DCM (3×5 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure to give title compound (193 mg, 100% yield) as ayellowish oil.

Step 5—Tert-Butyl2-ethyl-4-[5-[2-[3-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy-anilino]pyrimidin-4-yl]-2-pyridyl]piperazine-1-carboxylate

To a solution of2-[2-[2-[2-[2-[5-[[4-[6-(4-tert-butoxycarbonyl-3-ethyl-piperazin-1-yl)-3-pyridyl]pyrimidin-2-yl]amino]-2,3-dimethoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]aceticacid (192 mg, 250 umol),(2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (129 mg, 300 umol, IntermediateCI), and DIPEA (96.9 mg, 750 umol) in DMF (5 mL) was added HATU (114 mg,300 umol) at 0° C. The reaction mixture was then allowed to warm to rtand stirred for 16 hours. On completion, the reaction mixture wasconcentrated under reduced pressure to remove DMF, then diluted withwater (15 mL) and extracted with DCM (3×10 mL). The combined organiclayers were dried over sodium sulfate, and concentrated in vacuo to givea residue. The residue was purified by reverse phase chromatography(0.1% FA in water) to give the title compound (210 mg, 71% yield). LC-MS(ESI⁺) m/z 1183.2 (M+H)⁺.

Step6—(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-[2-[5-[[4-[6-(3-ethylpiperazin-1-yl)-3-pyridyl]pyrimidin-2-yl]amino]-2,3-dimethoxy-phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide

To a solution of tert-butyl2-ethyl-4-[5-[2-[3-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-4,5-dimethoxy-anilino]pyrimidin-4-yl]-2-pyridyl]piperazine-1-carboxylate(210 mg, 177 umol) in MeOH (3 mL) was added HCl in dioxane (4 M, 5 mL).Then the mixture was stirred at rt for 15 mins. On completion, thereaction mixture was concentrated under reduced pressure to removesolvent to give a residue. The residue was purified by prep-HPLC(column: Luna C18 150*25 5u; mobile phase: [water (0.225% FA)-ACN]) togive the title compound I-202 (118 mg, 61% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 9.40 (s, 1H), 8.95 (s, 1H), 8.93 (d, J 1.6 Hz, 1H), 8.61(J=4.0 Hz, 1H), 8.42 (d, J=5.6 Hz, 1H), 8.32-8.22 (m, 2H), 7.47-7.34 (m,5H), 7.29 (d, J 5.6 Hz, 1H), 7.25 (d, J=6.4 Hz, 2H), 6.97 (d, J=9.6 Hz,1H), 4.55 (d, J=9.6 Hz, 1H), 4.47-4.32 (m, 4H), 4.29-4.19 (m, 2H),4.13-4.04 (m, 2H), 3.94 (s, 2H), 3.81-3.72 (m, 6H), 3.68-3.58 (m, 14H),3.13-3.04 (m, 1H), 2.98 (m, 1H), 2.83-2.73 (m, 1H), 2.67 (d, J=6.4 Hz,2H), 2.42 (3H), 2.10-2.01 (m, 1H), 1.94-1.84 (m, 1H), 1.49-1.43 (m, 2H),1.01-0.85 (m, 12H); LC-MS (ESI⁺) m/z 1083.2 (M+H)⁺.

Example 203: PBMC Degradation Assay

Protocol summary of PBMC degradation studies from compound treatmentthrough quantitation.

TABLE 13 Cell Culture Materials Reagent Vendor Catalogue no. 6 wellplate Falcon 353046 Frozen PBMCs AllCells PB006F, PB005F or PB004F RPMIGibco 11875-093 FBS, certified one-shot Gibco A31604-02 Pen/Strep 1000units/mL Gibco 10378016 DMSO Sigma D8418-50 mL 2.0 mL centrifuge tubesCorning 311-10-051 PBS Gibco 10010-023

PBMC culture medium: Human peripheral blood mononuclear cells (PBMCs):RPMI+10% FBS (Heat-inactivated)+1% P/S.

TABLE 14 Lysate preparation and Western Reagents. Reagent VendorCatalogue no. LDS Sample Buffer (4×) Life NP0008 Technologies ReducingAgent (10×) Invitrogen NP0009 Molecular Grade diH2O Corning 46-000-CV 96well PCR plate Eppendorf 951020346 EA SDS-Page protein gel (4-12%Invitrogen WG1402BOX Bis-Tris) 20 well 20× MES running buffer (20×)Invitrogen NP0002 TransBlot Turbo RTA Midi LF BioRad 1704275 PVDFtransfer kit, for 40 blots 10× RIPA buffer Cell Signaling 9806Technologies HALT Protease and Thermo 1861281 Phosphatase InhibitorCocktail Scientific (100×) Odyssey Blocking buffer (TBS) Licor 927-50000TBST 10× Cell Signaling 9997 Technologies Molecular Weight Markers Licor928-40000

TABLE 15 Antibodies. Antibody Vendor Catalogue no. IRAK1 Cell Signaling4504S Technologies IRAK4 Cell Signaling 4363S Technologies IRAK3 CellSignaling 4369S Technologies MYD88 Abcam 133739 Actin Licor 926-42212Goat anti-rabbit IRDye 800CW Licor 926-32211 Goat anti-mouse IRDye 680CWLicor 926-68070

TABLE 16 Equipment. Equipment Vendor Catalogue no. XCell Surelock MidiCell Invitrogen WR0100 TransBlot Turbo transfer system BioRad 1704150Odyssey CLx Licor

Protocol Summary

Frozen human PBMCs were thawed into culture medium.

A cell count/viability assessment by trypan blue exclusion wasperformed. Cells were cultured at a minimum of 2.5×106 c/mL.

PBMCs were incubated @ 37° C./5% CO₂ and allowed to rest overnight.

Following overnight recovery, a cell count/viability assessment bytrypan blue exclusion was performed. Cells densities were adjusted backto 2.5×10⁶ c/mL (proceed with plating only if viability>80%).

In a 6 well plate, 2.0 mL of cells were added to each well for a minimumof 5×10⁶ CT per treatment condition. Compounds dilutions were preparedfrom 20 mM stock and were added at a final 1000× dilution (0.1% DMSOconcentration).

At the end of treatment, cells were harvested and spun @ 1800 rpm for 5min. 1×PBS wash and spun again @ 1800 rpm for 5 min. Cell pellets werefrozen and stored at −80° C. until further processing.

Lysates were generated by resuspending in lysis buffer. Proteinquantification was performed with a BCA kit.

20 μg of protein were loaded per lane and run on a 26-well 4-12%Bis-Tris SDS-page gel.

Transfers were performed on PVDF membranes using the BioRad Mixed MWturbo program for 7 min.

Membranes were blocked for one hour on a rocker at room temperature.

Primary antibodies were incubated overnight at 4° C. on a rocker.

Membranes were washed 3×TBST, 5 min each.

Secondaries were added and incubated for one hour on a rocker at roomtemperature.

Membranes were washed 3×TBST, 5 min each and rinsed well with deionizedH₂O. Membranes were scanned using the Licor Odessey CLx and bands werequantified using Image Studio Lite Version 5.2 software.

PBMC results at 4 hours. The letter codes indicate the percentage ofIRAK4 degraded after 4 hours: A (>0 degradation), B (>0-0 degredation)and C (<0 degredation)

TABLE 17 PBMC % IRAK4 Degradation Results. Compound PBMC Number % IRAK4Degradation I-53 A I-104 C I-106 A I-108 C I-109 B I-109 B I-110 A I-111B I-112 A I-116 A I-117 A I-127 A I-128 A I-130 A I-132 B I-132 C I-133B I-134 C I-141 A I-144 A I-145 C I-146 A I-150 A I-152 C I-154 B I-155C I-156 C I-157 C I-158 C I-159 A I-171 A I-172 A I-179 C I-180 A I-181B I-182 B I-183 B I-185 A I-186 C

Example 204: THP-1 and OCI-LY-10 Degradation Assay

Methods

Compound Treatment:

Compounds were reconstituted in DMSO to make stock solutions atconcentration of 60 mM. THP-1 and OCI-LY10 cells were maintained inRPMI-1640 medium containing 10% FBS, 0.5 μM 2-ME or 20% FBS, 55 μM 2-ME,and 1% L-Glutamine respectively.

Cells were seeded into 6-well plates with 5e6 cells per well. 200 μL ofdiluted compounds were added to cells to the final concentration of0.003-10 μM. After 4 or 24 hour-incubation at 37° C., cells werecollected into 2 mL Eppendorf tubes and centrifuged at 1,000 rpm for 5min. The cell pellets were washed with 1×DPBS once and resuspended in 60μL lysis buffer. The cells were lysed on ice for 10 min, thencentrifuged at 14,000 rpm for 10 min at 4° C. and the supernatants werecollected for western blots. For THP-1 cells, the lysis buffer contained40 mM pH 7.4 HEPES, 140 mM NaCl, 2.5 mM EDTA, 1% NP-40, 0.1% SDS, andprotease inhibitor cocktail (Roche, Cat. No. 05892791001). For OCI-LY10cells, RIPA buffer (Thermo Fisher, 89900) with Halt Protease andPhophatase Inhibitor Cocktail (Thermo Fisher, 78446) was applied.

Protein Concentration Determination:

The protein concentration of cell lysates was quantified with Pierce™BCA Protein Assay Kit (Pierce, 23227). Albumin standards at differentconcentrations were prepared, involving 2,000 ug/mL, 1,500 ug/mL, 1,000ug/mL, 750 ug/mL, 500 ug/mL, 250 ug/mL, 125 ug/mL, and 25 ug/mL. BCAworking reagents were prepared by mixing BCA reagent A with reagent B in50:1 ratio. 200 μL of the BCA working reagents were added to 25 μL ofBCA standard or cell lysates in microplate, and mixed thoroughly on aplate shaker for 30 seconds. After incubation at 37° C. for 30 min, theabsorbance of samples at 562 nm were measured with EnVision PlateReader.

Western Blot Assay:

Protein lysates were prepared in NuPAGE™ LDS sample buffer and NuPAGE™sample reducing agent, and incubated at 95° C. for 5 min. For westernblots, 20-25 μg of total proteins were resolved in 4-12% Bis-Tris gels(Introgen, WG1403A) or 10% Bis-Tris Midi gels (Invitrogen, WG1202BOX)running with 1×MOPS SDS running buffer (Invitrogen, NP0001) or 1×MES SDSrunning buffer (Invitrogen, NP0002). The proteins were transferred tolow fluorescence PVDF membranes using the Trans-Blot Turbo TransferSystem. Membranes were then blocked in Odyssey blocking buffer at RT for1 h followed by primary incubation at 4° C. overnight. The primaryantibodies were IRAK1 rabbit monoclonal antibody (CST, #4504S, 1:500),IRAK3 rabbit polyclonal antibody (CST, #4369, 1:500), IRAK4 rabbitpolyclonal antibody (CST, #4363S, 1:1,000), MyD88 rabbit monoclonalantibody (Abcam, Ab133739, 1:2,000), R-actin mouse monoclonal antibody(Sigma, A5441, 10,000), and Gapdh mouse monoclonal antibody (Millipore,MAB374, 1:5,000). Membranes were washed three times with 1×TBST, andthen incubated with IR Dye 800 CW Goat anti-rabbit (Licor, #926-32211)and IR Dye 700 CW Goat anti-mouse (Licor, #926-68070) secondaryantibodies in 1:10,000 dilution at RT for 1 h. The western blot imageswere obtained using Odyssey Imaging System.

THP-1 results at 24 hours. The letter codes indicate the percentage ofIRAK4 degraded after 24 hours: A (>50% degradation), B (>20-50%degredation) and C (<20% degredation)

TABLE 18 THP-1 % IRAK4 Degradation Results. Compound THP-1 24 h Name %IRAK4 Degradation I-1 B I-2 C I-3 C I-4 A I-5 B I-6 B I-7 B I-8 C I-10 CI-11 C I-12 C I-13 C I-14 C I-15 A I-16 C I-19 C I-25 B I-30 C I-40 CI-43 C I-47 B I-48 B I-49 B I-50 B I-51 C I-52 C I-55 C I-58 C I-96 CI-97 B I-98 B I-99 C I-100 B I-119 B I-120 C I-122 C I-162 A I-163 CI-164 C I-165 C I-189 C I-194 C I-195 C I-198 C I-199 C I-200 C I-203 B

OCI-LY-10 results at 4 hours. The letter codes indicate the percentageof IRAK4 degraded after 4 hours: A (>50% degradation), B (>20-50%degredation) and C (<20% degredation)

TABLE 19 OCI-LY-10 % IRAK4 Degradation Results. Compound OCI-LY10 Name %IRAK4 Degradation I-9 C I-17 C I-18 B I-21 C I-22 C I-26 C I-27 C I-29 CI-31 C I-32 C I-33 C I-34 C I-35 C I-36 C I-37 C I-38 C I-39 C I-41 CI-42 C I-44 B I-45 C I-46 C I-54 C I-56 C I-57 C I-59 C I-60 C I-61 CI-62 C I-63 C I-64 C I-65 C I-66 C I-67 C I-68 C I-69 C I-70 C I-71 CI-72 C I-73 C I-74 C I-75 C I-76 C I-77 C I-78 C I-79 C I-80 C I-81 CI-82 C I-83 C I-84 C I-85 C I-86 C I-87 C I-88 C I-89 C I-90 B I-91 CI-92 A I-93 C I-94 B I-95 C I-101 C I-102 C I-103 C I-105 A I-107 CI-113 C I-114 C I-115 B I-118 C I-121 C I-123 C I-124 C I-125 C I-126 BI-129 C I-131 C I-135 B I-136 B I-137 B I-138 A I-139 B I-140 B I-142 BI-143 B I-147 A I-148 B I-149 A I-151 A I-153 C I-160 C I-161 C I-169 CI-170 B I-173 C I-174 C I-175 C I-176 C I-177 C I-178 C I-184 C I-187 BI-188 C I-204 C I-205 C I-207 C I-208 C I-209 C I-210 A

OCI-LY-10 results at 4 hours. The letter codes for % IRAK4 degradationindicate the percentage of IRAK4 degraded after 4 hours across threedifferent concentrations: A (>50% degradation), B (>20-50% degredation)and C (<20% degredation).

TABLE 19a OCI-LY-10 % IRAK4 Degradation OCI-LY10 OCI-LY10 OCI-LY10 %IRAK4 % IRAK4 % IRAK4 Compound Degradation Degradation Degradation Name(0.01 uM) (0.1 uM) (1 uM) I-683 C B A I-211 B B B I-212 B A A I-215 A AA I-219 A A A I-220 B B B I-221 B B A I-222 A A A I-224 B A A I-225 C AA I-226 B A A I-227 B A A I-228 A A A I-229 C C C I-230 C C C I-231 A AA I-233 C A A I-234 C B B I-235 C A A I-236 C B A I-238 C B A I-239 C CC I-240 B B B I-241 B A A I-242 B A A I-243 C C C I-244 C B B I-245 C BA I-246 C A A I-247 B A A I-248 B A A I-249 C A A I-250 C A A I-252 B AA I-254 C C B I-255 C C C I-256 B A A I-257 C C C I-258 C B C I-259 C CC I-260 C C C I-262 C B B I-263 C C C I-264 C C C I-265 B A A I-266 C AA I-267 C A B I-269 C B A I-270 C B A I-272 C B A I-275 C B A I-276 C BA I-277 C A A I-278 C B A I-279 C A A I-281 C A A I-282 C C C I-283 A AA I-284 C C C I-285 C C B I-287 C C B I-288 C C A I-290 B B B I-297 C CC I-302 B A A I-303 B A A I-304 C C C I-305 A A A I-306 C B B I-307 C CC I-308 B A A I-309 B A A I-310 C A A I-311 C A A I-312 C A A I-313 C BC I-313 B A A I-314 C B B I-315 C C B I-316 B B B I-317 C C B I-318 C AB I-319 B A A I-320 C B B I-321 B A A I-322 C C A I-323 B A A I-324 B AB I-325 B A A I-326 B C C I-327 C B A I-328 A A A I-329 B A A I-330 C AA I-331 C B C I-332 A A A I-333 C C C I-335 C C A I-336 C C B I-337 C AA I-338 C B B I-339 C B A I-340 C A A I-341 C A A I-342 C B A I-343 C BA I-344 C A A I-345 C A A I-346 B A A I-347 C A A I-348 C C A I-349 C BA I-350 C C B I-351 C C A I-352 C C C I-353 C C C I-354 C A A I-355 B BC I-356 C C C I-357 C C C I-358 C C C I-359 C C C I-360 B C C I-361 C CC I-362 C B A I-363 C C C I-364 C C C I-365 C C C I-366 C C C I-367 B BA I-369 B B B I-370 C B B I-371 C C B I-372 C C C I-372 C C C I-374 C BB I-375 B B B I-376 B A A I-377 C C B I-378 C C A I-380 C C C I-381 B AA I-382 C C B I-383 C C A I-385 C B B I-386 C B A I-387 C C B I-389 C CA I-392 B A A I-393 C A A I-394 C A A I-395 C B B I-397 B A A I-424 B BB I-425 B A A I-426 C C C I-427 B A A I-434 C C C I-435 C C C

Example 204a: OCI-LY-10 DC₅₀

A MSD assay was run to determine the concentration of compound requiredto degrade 50% of protein (DC₅₀).

MSD Assay DC₅₀ Protocol

Day 1

Compounds were reconstituted to 10 mM in stock solutions. The stocksolutions were diluted to 5 mM and 45 μL of each dilution wastransferred to a 384 pp-plate. A 3 fold, 8-point serial dilution wasperformed by transferring 15 μL of compound into 30 μL DMSO using Janus.

20 nL of each compounds were added into each well of a 96-well plate(Corning3799).

OCI-Ly10 cells were seeded into the 96-well plate at 3.0*10e⁵ cells/100μL/well.

The cell plate was shaken at 720 rpm for 5 min and incubated for 4 hr.

The 100 μL of cells were transferred into the 96-PCR plate and spun downat high speed for 5 mins.

The supernatant was discarded and 100 μL of RIPA lysis buffer withproteinase inhibitors was added per well. The plate was then sealed andshaken at 600 rpm and 4° C. for about 20 min.

The plate was then spun down at high speed (about 3200 g) for 30 min andthen frozen in a −80° C. fridge.

A bare MSD plate (L15XA-3) was coated with 2 μg/mL of capture antibody(mouse Anti-IRAK4 antibody [2H9], ab119942) in PBS to 40 μL/well andincubated overnight at 4° C.

Day 2

The MSD coated plate was washed 3×(150 μL/well) with 1×TBST (CST#9997S).

The MSD plate was then blocked with 150 μL of blocking buffer [3%Blocker A (MSD, R93BA-4) in TBST]/well and shaken for 1 hr at RT and 600rpm.

The MSD plate was washed 3×(150 μL/well) with 1×TBST. The sample RIPAlysates were then added to the MSD plate (50 μL/well) and shaken for 1hr at RT and 600 rpm.

The MSD plate was washed 3×(150 μL/well) with 1×TBST and the primarydetection antibody (Rabbit Anti-IRAK4 antibody [Y279], ab32511) wasadded to a final concentration of 1 μg/ml with 25 μL/well. The plate wasthen shaken for 1 hr at RT and 600 rpm.

The MSD plate was washed 3×(150 μL/well) with 1×TBST and the secondarydetection antibody, SULFO-TAG anti-species antibody (Anti RabbitAntibody (R32AB-5) MSD,R32AB-1) was added to a volume of 25 μL/well at afinal concentration of 1 μg/ml. The plate was then shaken for 1 hr at RTand 600 rpm.

The MSD plate was then washed 3×(150 μL/well) with 1×TBST.

1×MSD reading buffer was then added (150 μL/well) and the plate wasdiluted with 4× water. (MSD, R92TC-2)

The MSD instrument was then read.

Data Analysis

The remaining activity was calculated following the formula below:

${{Relative}{Level}{of}{IRAK}4(\%)} = {100\% \times \frac{\begin{matrix}{{{MSD}{Signal}_{Sample}} -} \\{{MSD}{Signal}_{NC}}\end{matrix}}{\begin{matrix}{{{MSD}{Signal}_{PC}} -} \\{{MSD}{Signal}_{NC}}\end{matrix}}}$

Calculate

The DC₅₀ was calculated by fitting the Curve using Xlfit (v5.3.1.3),equation 201:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogIC50−X)*HillSlope))

OCI-LY-10 DC₅₀ results. The letter codes for IRAK4 DC₅₀ indicate theconcentration of compound required to degrade 50% of protein: A (<0.05μM), B (0.05-0.1 μM), C (0.1-0.5 μM), D (0.5-1.0 μM), and E (>1.0 μM).

TABLE 19b OCI-LY-10 % IRAK4 DC₅₀ Results Compound Name OCI-LY10 IRAK4DC₅₀ (μM) I-213 A I-214 E I-218 E I-219 A I-224 A I-225 A I-227 A I-228A I-231 A I-235 B I-240 E I-241 A I-242 A I-251 A I-252 A I-253 A I-255E I-258 E I-261 C I-262 E I-265 A I-266 A I-267 B I-268 A I-269 A I-270C I-271 C I-272 C I-273 B I-274 C I-276 B I-277 B I-278 B I-279 B I-280A I-281 B I-283 A I-284 E I-286 E I-287 E I-288 B I-289 E I-290 E I-292E I-293 E I-294 E I-295 E I-296 E I-297 E I-299 E I-300 E I-301 E I-302A I-305 A I-308 B I-313 A I-319 A I-320 E I-321 A I-332 A I-334 B I-344B I-350 E I-351 C I-352 E I-360 E I-366 E I-371 E I-381 A I-384 D I-386C I-387 E I-389 D I-390 C I-391 C I-392 B I-393 C I-394 C I-395 E I-396B I-397 A I-398 C I-399 A I-400 A I-401 A I-402 E I-403 B I-404 A I-405A I-405 A I-406 A I-407 A I-408 E I-411 A I-412 E I-413 E I-414 C I-415E I-416 E I-417 E I-419 C I-420 E I-421 C I-422 E I-423 E I-427 A I-428A I-429 E I-432 E I-436 E I-437 E I-438 E I-440 E I-441 E I-442 E I-444B I-445 B I-446 C I-447 B I-449 E I-456 E I-459 A I-460 A I-461 A I-462A I-463 E I-470 A I-472 E I-473 A I-475 A I-476 A I-477 A I-478 B I-479A I-487 A I-488 A I-489 A I-490 A I-491 B I-495 A I-504 A I-506 A I-508A I-509 A I-513 A I-514 A I-517 A I-522 E I-523 B I-524 E I-525 E I-529B I-530 A I-532 A I-534 A I-535 A I-536 A I-537 A I-539 D I-542 A I-543A I-545 A I-548 A I-549 A I-550 A I-551 A I-552 A I-553 D I-554 E I-555D I-556 D I-558 A I-559 E I-564 C I-567 A I-568 A I-572 A I-574 A I-576A I-579 C I-580 B I-583 A I-584 A I-585 A I-587 A I-588 A I-589 A I-590A I-592 A I-593 A I-599 C I-614 B I-692 E I-684 A I-685 A I-699 C I-700A I-689 A I-690 A I-519 D I-520 D I-521 E I-680 E I-681 D I-682 E

Example 204b: OCI-LY-10 EC₅₀

A CTG cell viability assay using OCI-LY-10 cells was run to determinecompound-mediated cell viability (EC₅₀).

Cell Viability Protocol

Compound-mediated viability effect on OCI-LY10 was quantitativelydetermined using the CellTiter-Glo® Luminescent Cell Viability Assay kitfrom Promega (Catalog number G7570) following manufacturer's recommendedprocedures. Briefly, OCI-LY10 cells were seeded into 384 well plates(Grenier Bio-One, Catalog number 781080) with a density of 10,000 cellsper well. Compounds were then added to the assay plate with final topconcentration of 10 μM and 1:3 dilution series with total of 9 doses.The final DMSO concentration was normalized to 0.2%. The assay plateswere incubated at 37° C. for 4 days under 5% CO₂. Then the assay platewas equilibrated at room temperature for 10 minutes. To determine cellviability, 30 μL CellTiter Glo reagent was added to each well and theassay plate was centrifuged at 1000 rpm for 30 second, incubated at roomtemperature for 10 min, and analyzed by detecting the luminescence usinga multimode plate reader (EnVision 2105, PerkinElmer). The data was thenanalyzed by software Prism 7.0 from GraphPad and the dose responsecurves were fit using a three-parameter logistic equation to calculateEC₅₀.

OCI-LY-10 EC₅₀ results. The letter codes for IRAK4 EC₅₀ indicate theconcentration of compound required to affect 50% of cells: A (<0.05 μM),B (0.05-0.1 μM), C (0.1-0.5 μM), D (0.5-1.0 μM), and E (>1.0 μM).

TABLE 19c OCI-LY-10 IRAK4 EC₅₀ Results Compound Name OCI-LY10 IRAK4 EC₅₀(μM) I-448 C I-449 E I-455 E I-456 E I-457 E I-458 B I-459 A I-460 AI-461 A I-462 A I-463 E I-464 E I-465 E I-466 E I-467 E I-468 E I-469 EI-470 A I-471 E I-472 E I-473 B I-475 A I-476 C I-477 A I-478 C I-479 AI-481 B I-482 C I-483 E I-484 E I-485 E I-487 B I-488 A I-489 D I-490 AI-491 A I-494 E I-495 D I-504 A I-506 A I-508 B I-509 A I-513 A I-514 AI-515 D I-517 E I-522 E I-523 A I-524 E I-525 E I-526 E I-527 E I-528 EI-529 B I-530 A I-531 A I-532 D I-533 D I-534 E I-535 E I-536 A I-537 AI-538 E I-539 A I-540 A I-541 E I-542 A I-543 A I-544 E I-545 A I-548 AI-549 A I-550 A I-551 A I-552 A I-553 E I-555 E I-556 E I-558 A I-559 DI-560 E I-563 E I-564 E I-567 D I-568 C I-572 C I-573 E I-574 A I-575 CI-576 A I-578 D I-579 E I-580 A I-581 C I-582 A I-583 A I-584 B I-585 AI-587 A I-588 A I-589 A I-590 A I-592 A I-593 C I-595 B I-596 E I-597 CI-598 A I-599 A I-614 C I-617 D I-691 E I-692 E I-694 E I-684 A I-685 AI-699 A I-700 B I-688 E I-689 D I-690 E I-519 D I-520 E I-521 E I-680 EI-682 E

TABLE 20 Compounds synthesized via Method 11 with the addition ofvarious amines to fluoride Intermediate R in Step 1, followed bycoupling with various acids in Step 3. LCMS Step 1 Step 3 (ES+)Intermediate Intermediate m/z Ex-# I-# Amine Acid (M + H)⁺ 1HNMR (400MHz, DMSO-d₆) δ  205^(a) I-683 FQ EG 905.0 11.10 (s, 1H), 9.98 (s, 1H),9.04-8.95 (m, 2H), 8.65 (t, J = 5.2 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H),8.05-8.00 (m, 4H), 7.66 (s, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.20-7.15 (m,2H), 7.13-7.07 (m, 2H), 7.04 (d, J = 6.8 Hz, 2H), 6.88 (t, J = 5.6 Hz,1H), 5.05 (dd, J = 5.4, 12.8 Hz, 1H), 4.37 (d, J = 5.6 Hz, 2H), 4.00 (t,J = 6.8 Hz, 2H), 3.26-3.25 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.94- 2.83(m, 1H), 2.60-2.54 (m, 2H), 2.05- 1.94 (m, 3H), 1.10-1.02 (m, 1H),0.48-0.43 (m, 2H), 0.24-0.21 (m, 2H) 206 I-211 tert-butyl N- FX 837.511.08 (s, 1H), 10.03 (s, 1H), 8.98 (s, [2-(2-aminoethoxy)- 1H), 8.91 (s,1H), 8.62 (t, J = 5.6 Hz, ethyl]carbamate 1H), 8.16 (d, J = 5.2 Hz, 1H),8.04- CAS# 127828-22-2) 7.92 (m, 4H), 7.59-7.53 (m, 1H), 7.47- 7.18 (m,1H), 7.17-7.00 (m, 5H), 6.63 (t, J = 5.6 Hz, 1H), 5.10-4.98 (m, 1H),3.69-3.63 (m, 2H), 3.63-3.58 (m, 2H), 3.53-3.43 (m, 4H), 3.19 (t, J =6.0 Hz, 2H), 2.95-2.79 (m, 1H), 2.61-2.52 (m, 2H), 2.08-1.96 (m, 1H),1.12-1.01 (m, 1H), 0.49-0.42 (m, 2H), 0.27-0.19 (m, 2H) 207 I-212tert-butyl N- FX 991.0 11.08 (s, 1H), 10.03 (s, 1H), 8.98 (s,[2-[2-[2-[2-(2- (M + 23)⁺ 1H), 8.92 (s, 1H), 8.63 (t, J = 5.2 Hz,aminoethoxy)-ethoxy]- 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.07-ethoxy]ethoxy]- 7.95 (m, 4H), 7.61-7.53 (m, 1H), 7.47- ethyl]carbamate7.17 (m, 1H), 7.15-7.06 (m, 3H), (CAS# 811442-84-9) 7.06-7.00 (m, 2H),6.59 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 3.63-3.58 (m,2H), 3.56-3.48 (m, 14H), 3.47-3.42 (m, 4H), 3.18 (t, J = 6.0 Hz, 2H),2.94-2.82 (m, 1H), 2.63- 2.52 (m, 2H), 2.06-1.97 (m, 1H), 1.12-1.02 (m,1H), 0.50-0.41 (m, 2H), 0.27-0.20 (m, 2H) 208 I-213 KN DF 888.5 11.10(s, 1H), 11.01 (s, 1H), 9.04 (s, 1H), 9.02 (s, 1H), 8.63 (t, J = 52 Hz,1H), 8.17 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 8.08 (d, J = 8.8 Hz, 2H),8.03 (d, J = 8.8 Hz, 2H), 7.79 (s, 1H), 7.57 (dd, J = 7.2, 8.4 Hz, 1H),7.18 (t, J = 5.2 Hz, 1H), 7.15-7.09 (m, 2H), 7.06- 6.99 (m, 2H), 6.60(t, J = 5.2 Hz, 1H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H), 3.53 (t, J = 5.2Hz, 2H), 3.53-3.47 (m, 8H), 3.20 (t, J = 6.0 Hz, 2H), 2.93-2.83 (m, 1H),2.63-2.53 (m, 2H), 2.09-1.98 (m, 1H), 1.79-1.72 (m, 2H), 1.13- 1.00 (m,1H), 0.49-0.42 (m, 2H), 0.25- 0.21 (m, 2H) 209 I-214 tert-butyl N- KR929.1 11.09 (s, 1H), 10.82 (s, 1H), 9.02 (s, [2-[2-[2-[2-[2- 1H),8.44-8.38 (m, 2H), 8.25-8.23 (m, (2-aminoethoxy) 2H), 7.56(dd, J = 7.2Hz, J = 8.4 Hz, ethoxy]-ethoxy]ethoxy]- 1H), 7.41 (s, 1H), 7.25 (d, J =5.6 Hz, ethoxy]ethyl-carbamate 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.01 (d,(CAS# 189209-27-6) J = 6.8 Hz, 1H), 6.58 (bs, 1H), 5.06- 5.03 (m, 1H),4.37-4.36 (m, 2H), 3.93- 3.91 (m, 6H), 3.53-3.44 (m, 22H), 2.88 (m, 1H),2.60-2.54 (m, 2H), 2.03-2.01 (m, 1H) ^(a)For varations in Method 11, seeTable 9 footnotes.

TABLE 21 Compounds synthesized via Method 12 with the coupling ofvarious amines and acids in Step 1. LCMS Step 1 Step 1 (ES+)Intermediate Intermediate m/z Ex-# I-# Amine Acid (M + H)⁺ 1HNMR (400MHz, DMSO-d6) δ  210^(a) I-215 OK FI 888.4 11.1 (s, 1H), 10.3 (s, 1H),9.00 (s, 1H), 8.84 (s, 1H), 8.61 (t, J = 5.2 Hz, 1H), 8.33 (s, 3H), 8.26(d, J = 5.2 Hz, 1H), 8.05-8.00 (m, 2H), 7.99-7.95 (m, 2H), 7.68-7.62 (m,1H), 7.60-7.54 (m, 1H), 7.24 (s, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.03 (d,J = 7.2 Hz, 1H), 6.61 (s, 1H), 5.11-5.00 (m, 1H), 4.28- 4.19 (m, 4H),3.54-3.46 (m, 12H), 2.95-2.81 (m, 1H), 2.63-2.57 (m, 1H), 2.56-2.54 (m,1H), 2.07-1.99 (m, 1H) 211 I-216 CT CN 989.9 11.12 (s, 1H), 11.01 (s,1H), 9.04 (d, J = 2.4 Hz, 2H), 8.64 (t, J = 5.2 Hz, 1H), 8.26 (d, J =5.2 Hz, 1H), 8.18-8.07 (m, 3H), 8.07-8.00 (m, 2H), 7.84- 7.74 (m, 3H),7.74-7.67 (m, 2H), 7.27 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H), 5.13 (dd, J =5.2, 12.8 Hz, 1H), 4.33-4.20 (m, 2H), 3.59-3.37 (m, 18H), 2.95- 2.76 (m,3H), 2.65-2.57 (m, 2H), 2.11- 1.99 (m, 1H), 1.90-1.82 (m, 2H) 212 I-217CS CN 985.6 11.14 (s, 1H), 11.00 (s, 1H), 9.03 (m, 2H), 8.65 (t, J = 5.2Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 8.18-8.08 (m, 3H), 8.06-8.00 (m, 2H),7.98-7.87 (m, 3H), 7.77 (s, 1H), 7.70 (t, J = 6.8 Hz, 1H), 7.27 (s, 1H),7.22-7.10 (m, 1H), 5.16 (dd, J = 5.2, 12.8 Hz, 1H), 4.45 (s, 2H),4.31-4.19 (m, 2H), 3.69-3.50 (m, 16H), 2.93-2.84 (m, 1H), 2.62 (m, 1H),2.57 (m, 1H), 2.10-2.02 (m, 1H) 213 I-218 FP EG 896.1 11.11 (s, 1H),9.99 (s, 1H), 9.01 (s, 1H), 8.98 (s, 1H), 8.75-8.74 (m, 1H), 8.16 (d, J= 5.2 Hz, 1H), 8.06-7.99 (m, 4H), 7.63-7.52 (m, 1H), 7.14- 7.08 (m, 3H),7.06-7.00 (m, 2H), 6.64- 6.52 (m, 1H), 5.08-5.02 (m, 1H), 3.30-3.26 (m,6H), 3.22-3.13 (m, 2H), 2.92-2.83 (m, 1H), 2.74-2.70 (m, 2H), 2.62-2.52(m, 2H), 2.05- 2.00 (m, 1H), 1.80-1.72 (m, 2H), 1.65- 1.54 (m, 4H),1.10-1.04 (m, 1H), 0.48-0.43 (m, 2H), 0.25-0.20 (m, 2H) 214 I-219 FR CN955.6 11.11 (s, 1H), 11.03 (s, 1H), 9.05 (s, 1H), 9.02 (s, 1H), 8.37 (s,1H), 8.26 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H),7.97 (d, J = 8.8 Hz, 2H), 7.80 (s, 1H), 7.72 (t, J = 6.4 Hz, 1H),7.57-7.50 (m, 1H), 7.28 (s, 1H), 7.18 (dd, J = 1.2, 5.2 Hz, 1H), 7.11(dd, J = 2.8, 8.8 Hz, 1H), 7.00 (dd, J = 2.0, 7.2 Hz, 1H), 6.60-6.59 (m,1H), 5.07-5.02 (m, 1H), 4.32-4.20 (m, 2H), 3.63-3.25 (m, 10H), 2.97-2.80(m, 4H), 2.64-2.57 (m, 2H), 2.08- 1.96 (m, 1H), 1.63-1.61 (m, 2H), 1.51-1.39 (m, 2H), 1.32-1.21 (m, 2H) 215 I-220 OK EG 899.1 11.08 (s, 1H),9.96 (s, 1H), 9.00-8.96 (m, 1H), 8.98 (d, J = 4.4 Hz, 2H), 8.63 (t, J =5.2 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05-7.97 (m, 4H), 7.55 (t, J =7.6 Hz, 1H), 7.12-6.99 (m, 5H), 6.59 (t, J = 5.6 Hz, 1H), 5.05 (dd, J =5.2, 12.8 Hz, 1H), 3.65-3.54 (m, 8H), 3.46- 3.43 (m, 4H), 3.18 (t, J =6.0 Hz, 2H), 2.92-2.83 (m, 1H), 2.60-2.54 (m, 2H), 2.07-1.99 (m, 1H),1.11- 1.03 (m, 1H), 0.48-0.43 (m, 2H), 0.25- 0.20 (m, 2H) 216 I-221 FVEG 895.5 11.19 (s, 1H), 10.00 (s, 1H), 9.03- 8.97 (m, 2H), 8.61 (t, J =5.2 Hz, 1H), 8.36 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.06-7.98 (m, 4H),7.81-7.74 (m, 2H), 7.72-7.68 (m, 1H), 7.14-7.07 (m, 2H), 7.04 (d, J =5.2 Hz, 1H), 5.13 (dd, J = 5.2, 12.8 Hz, 1H), 3.31-3.32 (m, 4H), 3.18(t, J = 6.0 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.93-2.85 (m, 1H),2.64-2.61 (m, 2H), 2.59-2.56 (m, 1H), 2.55-2.53 (m, 1H), 2.10- 2.02 (m,1H), 1.86-1.76 (m, 2H), 1.59- 1.46 (m, 4H), 1.36-1.35 (m, 2H), 1.12-1.02(m, 1H), 0.49-0.42 (m, 2H), 0.25-0.21 (m, 2H) 217 I-222 FS EG 898.111.10 (s, 1H), 9.97 (s, 1H), 9.00-8.96 (m, 2H), 8.71-8.68 (m, 1H), 8.18(s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.06- 7.96 (m, 4H), 7.55 (t, J = 8.0Hz, 1H), 7.13-6.97 (m, 5H), 6.77-6.71 (m, 1H), 5.09-5.99 (m, 1H),3.57-3.52 (m, 4H), 3.49-3.44 (m, 4H), 3.21- 3.16 (m, 2H), 2.93-2.86 (m,1H), 2.85- 2.74 (m, 4H), 2.62-2.55 (m, 2H), 2.05-1.96 (m, 1H), 1.11-1.03(m, 1H), 0.48-0.42 (m, 2H), 0.25-0.20 (m, 2H) 218 I-223 EL FX 878.211.11 (s, 1H), 10.08 (s, 1H), 9.00 (s, 1H), 8.93 (s, 1H), 8.57 (t, J =52 Hz, 1H), 8.30 (s, 1H), 8.20-8.14 (m, 1H), 8.05-7.95 (m, 4H), 7.59 (t,J = 7.8 Hz, 1H), 7.46-7.19 (m, 1H), 7.16-7.11 (m, 2H), 7.07-7.01 (m,2H), 6.82 (t, J = 5.2 Hz, 1H), 5.06 (dd, J = 5.4, 12.8 Hz, 1H),3.37-3.19 (m, 8H), 2.95- 2.80 (m, 4H), 2.67-2.62 (m, 2H), 2.08- 2.00 (m,1H), 1.61-1.47 (m, 4H), 1.38 (d, J = 12 Hz, 2H), 1.14-1.02 (m, 1H),0.51-0.43 (m, 2H), 0.23 (q, J = 4.8 Hz, 2H) 219 I-224 FZ DF 887.5 11.12(s, 1H), 10.98 (s, 1H), 9.00 (s, 1H), 8.98-8.93 (m, 1H), 8.16 (d, J =5.2 Hz, 1H), 8.09 (s, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.80-7.69 (m, 3H),7.63 (s, 1H), 7.60-7.52 (m, 2H), 7.17 (t, J = 5.2 Hz, 1H), 7.12 (s, 1H),7.04-6.97 (m, 1H), 5.15-5.07 (m, 1H), 3.61- 3.49 (m, 10H), 3.18 (t, J =6.0 Hz, 2H), 3.09-3.02 (m, 2H), 2.99 (s, 3H), 2.93- 2.81 (m, 1H),2.64-2.55 (m, 2H), 2.09-2.00 (m, 1H), 1.90-1.76 (m, 2H), 1.12-1.01 (m,1H), 0.48-0.42 (m, 2H), 0.26-0.20 (m, 2H) 220 I-225 FZ FX 894.6 11.1 (s,1H), 10.0 (s, 1H), 8.98 (s, 1H), 8.86 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H),7.91 (d, J = 7.2 Hz, 2H), 7.73 (s, 2H), 7.66 (s, 1H), 7.57 (d, J = 6.4Hz, 2H), 7.46-7.16 (m, 1H), 7.15-7.08 (m, 2H), 7.05 (d, J = 5.2 Hz, 1H),5.17- 5.06 (m, 1H), 3.67-3.49 (m, 10H), 3.22-3.16 (m, 2H), 3.10-3.02 (m,2H), 3.00 (s, 3H), 2.94-2.82 (m, 1H), 2.64-2.57 (m, 1H), 2.57-2.53 (m,1H), 2.12-1.99 (m, 1H), 1.92-1.80 (m, 2H), 1.15-1.01 (m, 1H), 0.52- 0.43(m, 2H), 0.28-0.19 (m, 2H)  221^(b) I-226 FZ EE 818.4 11.12 (s, 2H),9.11 (s, 1H), 8.97 (s, 1H), 8.87 (d, J = 5.6 Hz, 2H), 8.15- 8.06 (m,1H), 8.06-7.95 (m, 4H), 7.80 (s, 1H), 7.73 (s, 2H), 7.66 (s, 1H), 7.58(d, J = 7.2 Hz, 2H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 3.66-3.49 (m,10H), 3.06 (s, 2H), 3.01 (s, 3H), 2.95-2.82 (m, 1H), 2.65-2.54 (m, 2H),2.11- 2.00 (m, 1H), 1.85 (s, 2H)  222^(b) I-227 GD EE 818.4 11.14-11.05(m, 2H), 9.10 (d, J = 2.0 Hz, 1H), 8.97 (s, 1H), 8.86 (d, J = 5.2 Hz,2H), 8.09 (s, 1H), 8.03 (s, 2H), 7.97 (d, J = 4.4 Hz, 2H), 7.82-7.63 (m,4H), 7.58 (d, J = 7.6 Hz, 2H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H),3.68-3.39 (m, 10H), 3.01 (s, 3H), 2.94-2.78 (m, 3H), 2.61-2.53 (m, 2H),2.10-2.01 (m, 1H), 1.86 (s, 2H) 223 I-228 GD DF 887.5 11.13 (s, 1H),10.99 (s, 1H), 9.10- 8.87 (m, 2H), 8.24-7.97 (m, 4H), 7.82- 7.53 (m,6H), 7.20 (t, J = 5.2 Hz, 1H), 7.13 (s, 1H), 7.01 (d, J = 5.6 Hz, 1H),5.12 (d, J = 8.8 Hz, 1H), 3.68- 3.39 (m, 12H), 3.01 (s, 3H), 2.90-2.72(m, 3H), 2.64-2.54 (m, 2H), 2.10- 2.01 (m, 1H), 1.85 (s, 2H), 1.07 (d, J= 6.4 Hz, 1H), 0.62-0.35 (m, 2H), 0.23 (d, J = 4.8 Hz, 2H) 224 I-229 GLDF 843.6 10.88 (s, 1H), 10.77 (s, 1H), 8.76 (s, 2H), 7.93 (d, J = 5.2Hz, 1H), 7.89- 7.76 (m, 3H), 7.58-7.41 (m, 4H), 7.34 (d, J = 8.0 Hz,2H), 6.96-6.85 (m, 2H), 6.77 (d, J = 4.8 Hz, 1H), 6.81- 6.74 (m, 1H),4.89 (dd, J = 5.2, 12.8 Hz, 1H), 3.31-3.45 (m, 4H), 3.22- 3.21 (m, 2H),2.95 (t, J = 6.0 Hz, 2H), 2.89-2.81 (m, 1H), 2.77 (s, 3H), 2.70- 2.58(m, 1H), 2.40-2.30 (m, 2H), 1.87-1.76 (m, 1H), 1.71-1.55 (m, 2H),0.89-0.77 (m, 1H), 0.22 (d, J = 8.0 Hz, 2H), 0.00 (d, J = 4.8 Hz, 2H)225 I-230 GS DF 883.6 10.89 (s, 1H), 10.82-10.65 (m, 1H), 8.86-8.66 (m,2H), 7.93 (d, J = 5.2 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H),7.54-7.28 (m, 6H), 6.94 (t, J = 5.2 Hz, 1H), 6.88 (s, 1H), 6.77 (d, J =5.6 Hz, 1H), 4.94-4.81 (m, 1H), 3.25-3.18 (m, 2H), 2.95 (t, J = 6.0 Hz,3H), 2.82-2.72 (m, 2H), 2.72-2.68 (m, 2H), 2.66-2.62 (m, 1H), 2.40- 2.31(m, 2H), 1.88-1.76 (m, 1H), 1.42-1.19 (m, 4H), 1.14-0.83 (m, 10H),0.81-0.76 (m, 1H), 0.25-0.18 (m, 2H), 0.03-0.00 (q, J = 4.8 Hz, 2H) 226I-231 GV CN 874.1 11.11 (s, 1H), 11.03 (s, 1H), 9.04 (d, J = 1.2 Hz,2H), 8.64 (t, J = 5.6 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 8.15 (s, 1H),8.12-8.07 (m, 2H), 8.05-8.00 (m, 2H), 7.79 (s, 1H), 7.71 (t, J = 6.4 Hz,1H), 7.29-7.24 (m, 2H), 7.18 (dd, J = 1.2, 5.2 Hz, 1H), 7.11 (d, J = 8.0Hz, 1H), 7.08-7.00 (m, 2H), 5.38 (dd, J = 5.6, 12.8 Hz, 1H), 4.28-4.20(m, 2H), 4.02-3.98 (m, 1H), 4.00 (t, J = 5.6 Hz, 1H), 3.69 (t, J = 5.6Hz, 2H), 3.58- 3.49 (m, 8H), 2.96-2.84 (m, 1H), 2.78- 2.70 (m, 1H),2.64-2.60 (m, 1H), 2.03-1.99 (m, 1H) 227 I-232 GU CN 843.4 11.01 (s,1H), 11.0 (s, 1H), 9.04 (s, 2H), 8.70-8.62 (m, 1H), 8.25 (d, J = 5.2 Hz,1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 8.01 (s,1H), 7.78 (s, 1H), 7.76-7.70 (m, 1H), 7.47- 7.73 (m, 1H), 7.46-7.40 (m,2H), 7.27 (s, 1H), 7.19-7.15 (m, 1H), 5.16- 5.08 (m, 1H), 4.49-4.40 (m,1H), 4.34-4.23 (m, 3H), 3.57-3.50 (m, 2H), 3.49-3.40 (m, 4H), 2.98-2.85(m, 1H), 2.72-2.67 (m, 2H), 2.63- 2.55 (m, 1H), 2.45-2.38 (m, 1H), 2.05-1.93 (m, 1H), 1.89-1.79 (m, 2H) 228 I-233 GX CN 923.4 11.12 (s, 1H),11.02 (s, 1H), 9.03 (d, J = (M + Na)⁺ 8.0 Hz, 2H), 8.69-8.61 (m, 1H),8.26 (d, J = 4.8 Hz, 1H), 8.12 (s, 1H), 8.10-8.05 (m, 2H), 8.05-8.00 (m,2H), 7.79-7.65 (m, 5H), 7.28 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 5.12(dd, J = 4.4, 12.0 Hz, 1H), 4.30-4.21 (m, 2H), 3.58-3.39 (m, 10H), 3.03(t, J = 7.2 Hz, 2H), 2.95-2.83 (m, 1H), 2.64- 2.57 (m, 1H), 2.56-2.54(m, 1H), 2.10- 2.01 (m, , 1H), 1.86-1.78 (m, 2H) 229 I-234 GW CN 857.011.12 (s, 1H), 11.01 (s, 1H), 9.07- 9.00 (m, 2H), 8.70-8.63 (m, 1H),8.28- 8.23 (m, 1H), 8.14 (s, 1H), 8.12- 8.07 (m, 2H), 8.06-8.01 (m, 2H),7.77 (s, 1H), 7.76-7.65 (m, 4H), 7.27 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H),5.16- 5.08 (m, 1H), 4.31-4.19 (m, 2H), 3.56- 3.50 (m, 2H), 3.49-3.43 (m,4H), 3.08 (t, J = 7.2 Hz, 2H), 2.93-2.82 (m, 1H), 2.64-2.54 (m, 2H),2.11-2.00 (m, 1H), 1.93-1.79 (m, 2H) 230 I-235 HA CN 1011.5 11.12 (s,1H), 11.01 (s, 1H), 9.04 (d, J = (M + Na)⁺ 3.2 Hz, 2H), 8.64 (t, J = 5.2Hz, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 8.12-8.08 (m, 2H),8.06-8.00 (m, 2H), 7.79-7.66 (m, 5H), 7.28 (s, 1H), 7.18 (dd, J = 1.2,5.2 Hz, 1H), 5.13 (dd, J = 52, 12.8 Hz, 1H), 4.33-4.19 (m, 2H),3.58-3.44 (m, 16H), 3.40 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H),2.94-2.84 (m, 1H), 2.63-2.55 (m, 2H), 2.10-2.02 (m, 1H), 1.88-1.78 (m,2H) 231 I-236 MN CN 985.5 11.14 (s, 1H), 11.00 (s, 1H), 9.03 (d, J = 2.4Hz, 2H), 8.65 (s, 1H), 8.52 (s, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.15-8.07 (m, 3H), 8.06-8.01 (m, 2H), 7.92- 7.83 (m, 3H), 7.77 (s, 1H), 7.71(t, J = 6.8 Hz, 1H), 7.27 (s, 1H), 7.18 (dd, J = 1.2, 5.2 Hz, 1H), 5.15(dd, J = 5.2, 12.8 Hz, 1H), 4.48 (s, 2H), 4.31-4.20 (m, 2H), 3.71 (dd, J= 3.6, 5.6 Hz, 2H), 3.56-3.53 (m, 8H), 3.50-3.40 (m, 5H), 2.95-2.88 (m,1H), 2.70-2.55 (m, 5H), 2.36-2.31 (m, 1H), 2.11-2.04 (m, 1H) 232 I-237HB DF 859.5 11.04-10.97 (m, 2H), 9.03 (s, 1H), 9.01 (s, 1H), 8.65 (t, J= 5.2 Hz, 1H), 8.20-8.12 (m, 2H), 8.11-8.05 (d, J = 8.8 Hz, 2H),8.04-7.98 (d, J = 8.8 Hz, 2H), 7.79 (s, 1H), 7.58-7.52 (m, 1H), 7.43 (d,J = 4.4 Hz, 2H), 7.17 (t, J = 5.2 Hz, 1H), 7.12 (s, 1H), 7.00 (dd, J =1.2, 5.2 Hz, 1H), 5.13 (dd, J = 4.8, 13.2 Hz, 1H), 4.49-4.40 (d, J =17.2 Hz, 1H), 4.34-4.24 (d, J = 17.2 Hz 1H), 3.58-3.54 (m, 4H),3.51-3.48 (m, 2H), 3.47-3.44 (m, 2H), 3.39 (t, J = 6.4 Hz, 2H), 3.19 (t,J = 6.4 Hz, 2H), 2.97-2.87 (m, 1H), 2.66-2.52 (m, 4H), 2.06-1.95 (m,1H), 1.84-1.77 (m, 2H), 1.14-1.01 (m, 1H), 0.53- 0.40 (m, 2H), 0.29-0.19(m, 2H) 233 I-238 HC DF 925.5 11.01 (s, 1H), 10.99 (s, 1H), 9.04 (s,(M + Na)⁺ 1H), 9.01 (s, 1H), 8.64 (s, 1H), 8.21- 8.13 (m, 2H), 8.12-8.07(m, 2H), 8.05- 7.99 (m, 2H), 7.78 (s, 1H), 7.58- 7.52 (m, 1H), 7.44 (d,J = 4.0 Hz, 2H), 7.20-7.14 (m, 1H), 7.13 (s, 1H), 7.01 (d, J = 4.8 Hz,1H), 5.17-5.08 (m, 1H), 4.47-4.40 (m, 1H), 4.32-4.27 (m, 1H), 3.57-3.52(m, 8H), 3.48- 3.44 (m, 6H), 3.25-3.09 (m, 2H), 3.04- 2.90 (m, 1H),2.66-2.55 (m, 1H), 2.55-2.54 (m, 1H), 2.42-2.41 (m, 2H), 2.04-1.99 (m,1H), 1.85-1.80 (m, 2H), 1.11-1.04 (m, 1H), 0.49- 0.43 (m, 2H), 0.26-0.20(m, 2H) 234 I-239 HE OM 799.4 10.87 (s, 1H), 10.71 (s, 1H), 8.69 (s,1H), 8.16 (s, 1H), 7.91 (d, J = 5.2 Hz, 1H), 7.52 (s, 1H), 7.34-7.29 (m,1H), 7.28 (s, 1H), 6.95-6.90 (m, 1H), 6.88- 6.85 (m, 2H), 6.78 (d, J =7.2 Hz, 1H), 6.75-6.73 (m, 1H), 6.36-6.30 (m, 1H), 4.84-4.78 (m, 1H),4.13- 4.08 (m, 2H), 3.60-3.55 (m, 2H), 3.37- 3.34 (m, 2H), 3.29-3.26 (m,6H), 3.24-3.17 (m, 4H), 2.97-2.93 (m, 2H), 2.66-2.59 (m, 1H), 2.40-2.35(m, 1H), 2.33-2.31 (m, 1H), 1.82- 1.74 (m, 1H), 0.86-0.80 (m, 1H), 0.24-0.21 (m, 2H), 0.02-0.01 (m, 2H) 235 I-240 HI OM 843.5 11.09 (s, 1H),10.94 (s, 1H), 8.93 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 7.74 (s, 1H),7.59-7.53 (m, 1H), 7.51 (s, 1H), 7.14 (t, J = 5.2 Hz, 1H), 7.12-7.08 (m,2H), 7.00-6.95 (m, 2H), 6.57 (t, J = 5.6 Hz, 1H), 5.10-5.00 (m, 1H),4.35 (t, J = 5.2 Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.62-3.56 (m, 2H),3.54-3.41 (m, 14H), 3.18 (t, J = 6.0 Hz, 2H), 2.93- 2.82 (m, 1H),2.62-2.53 (m, 2H), 2.07-1.97 (m, 1H), 1.11-1.01 (m, 1H), 0.49-0.42 (m,2H), 0.25-0.20 (m, 2H)  236^(b) I-241 OK MP 819.1 11.18-11.00 (m, 2H),9.09 (s, 1H), 9.02 (s, 1H), 8.70 (d, J = 5.6 Hz, 1H), 8.62 (t, J = 5.6Hz, 1H), 8.19-8.11 (m, 1H), 8.11-7.98 (m, 4H), 7.86-7.79 (m, 2H), 7.76(d, J = 4.8 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H),7.01 (d, J = 7.2 Hz, 1H), 6.59 (t, J = 6.0 Hz, 1H), 5.10-4.97 (m, 1H),3.65-3.52 (m, 8H), 3.48-3.42 (m, 4H), 2.93-2.81 (m, 1H), 2.61 (s, 3H),2.58-2.53 (m, 2H), 2.09-1.98 (m, 1H) 237 I-242 EL FX 878.1 11.09 (s,1H), 10.05 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.59-8.50 (m, 1H), 8.27(s, 2H), 8.16 (d, J = 5.2 Hz, 1H), 8.03-7.9 (m, 4H), 7.62-7.55 (m, 1H),7.47-7.17 (t, J = 50.0 Hz, 1H), 7.15- 7.01 (m, 5H), 6.85-6.78 (m, 1H),5.0- 5.1 (m, 1H), 3.40 (s, 2H), 3.30-3.24 (m, 1H), 3.21-3.15 (m, 2H),2.97-2.87 (m, 1H), 2.86-2.79 (m, 2H), 2.71- 2.56 (m, 4H), 2.07-1.96 (m,1H), 1.64- 1.44 (m, 4H), 1.40-1.30 (m, 2H), 1.14-1.01 (m, 1H), 0.48-0.42(m, 2H), 0.27-0.18 (m, 2H) 238 I-243 GW FX 836.4 11.12 (s, 1H), 10.06(s, 1H), 8.99 (s, 1H), 8.92 (s, 1H), 8.66 (t, J = 52 Hz, 1H), 8.16 (d, J= 5.2 Hz, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.95 (d, J = 8.8 Hz, 2H),7.78-7.71 (m, 2H), 7.70-7.64 (m, 1H), 7.32 (t, J = 54.0 Hz, 1H),7.14-7.08 (m, 2H), 7.04 (dd, J = 1.2, 5.2 Hz, 1H), 5.12 (dd, J = 5.6,12.8 Hz, 1H), 3.52 (t, J = 6.4 Hz, 2H), 3.45 (t, J = 6.0 Hz, 4H), 3.18(t, J = 6.0 Hz, 2H), 3.08 (t, J = 6.8 Hz, 2H), 2.94-2.82 (m, 1H),2.64-2.54 (m, 2H), 2.11-1.99 (m, 1H), 1.92-1.80 (m, 2H), 1.13-1.02 (m,1H), 0.50-0.41 (m, 2H), 0.27-0.18 (m, 2H) 239 I-244 GX FX 880.5 10.89(s, 1H), 9.82 (s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.45-8.37 (m, 1H),7.93 (d, J = 5.2 Hz, 1H), 7.81-7.75 (m, 2H), 7.74-7.69 (m, 2H), 7.53-7.47 (m, 2H), 7.45-7.41 (m, 1H), 7.24- 6.94 (m, 1H), 6.91-6.85 (m, 2H),6.83-6.77 (m, 1H), 4.89 (dd, J = 5.6, 12.8 Hz, 1H), 3.37-3.20 (m, 10H),2.95 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.71-2.62 (m, 1H),2.41- 2.38 (m, 1H), 2.36-2.34 (m, 1H), 1.86-1.77 (m, 1H), 1.62-1.53 (m,2H), 0.89-0.80 (m, 1H), 0.26-0.19 (m, 2H), 0.03-0.00 240 I-245tert-butyl N- FX 878.2 11.24-11.01 (m, 1H), 10.09 (s, 1H),[2-[5-[[2-(2,6- 9.00 (s, 1H), 8.93 (s, 1H), 8.69 (s, 1H),dioxo-3-piperidyl)- 8.34 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H),1,3-dioxo-isoindolin- 8.02 (d, J = 10.4 Hz, 3H), 7.58 (s, 1H),4-yl]amino]- 7.33 (s, 1H), 7.21-7.03 (m, 4H), 6.55 pentylamino]- (s,1H), 5.05 (s, 1H), 3.19 (s, 6H), 2.95- ethyl]carbamate 2.91 (m, 1H),2.87 (d, J = 14.8 Hz, (synthesized 2H), 2.83-2.80 (m, 1H), 2.78-2.74 viaSteps 1-4 (m, 1H), 2.68-2.65 (m, 2H), 2.04- of Example 144) 2.02 (m,1H), 1.66-1.33 (m, 6H), 1.08- 1.05 (m, 1H), 0.47 (d, J = 7.2 Hz, 2H),0.24 (s, 2H) 241 I-246 OK FX 881.5 11.10 (s, 1H), 10.05 (s, 1H), 8.99(s, 1H), 8.92 (s, 1H), 8.61 (t, J = 5.6 Hz, 1H), 8.17 (d, J = 5.6 Hz,1H), 8.08- 7.92 (m, 4H), 7.61-7.50 (m, 1H), 7.49- 7.16 (m, 1H),7.15-6.99 (m, 5H), 6.60 (t, J = 5.6 Hz, 1H), 5.06 (dd, J = 5.6, 12.8 Hz,1H), 3.64-3.56 (m, 7H), 3.46-3.43 (m, 5H), 3.20 (t, J = 6.0 Hz, 2H),2.94-2.83 (m, 1H), 2.69-2.56 (m, 2H), 2.09-1.99 (m, 1H), 1.17- 1.02 (m,1H), 0.52-0.43 (m, 2H), 0.29- 0.18 (m, 2H) 242 I-247 HK FX 936.1 11.10(s, 1H), 10.04 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.67-8.60 (m, 1H),8.16 (d, J = 5.4 Hz, 1H), 8.06-8.00 (m, 2H), 7.99-7.93 (m, 2H), 7.57 (t,J = 7.6 Hz, 1H), 7.47-7.17 (m, 1H), 7.16-6.98 (m, 5H), 6.63-6.55 (m,1H), 5.11-5.01 (m, 1H), 3.75 (d, J = 10.8 Hz, 1H), 3.65-3.51 (m, 6H),3.50- 3.36 (m, 4H), 3.35-3.27 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H),2.95-2.80 (m, 2H), 2.75-2.65 (m, 1H), 2.58-2.53 (m, 2H), 2.13-2.06 (m,1H), 2.04- 1.97 (m, 1H), 1.91-1.80 (m, 1H), 1.13- 1.02 (m, 1H),0.50-0.40 (m, 2H), 0.26-0.19 (m, 2H) 243 I-248 HO CN 902.5 11.08 (s,1H), 11.03 (s, 1H), 9.04 (s, 2H), 8.66 (t, J = 5.6 Hz, 1H), 8.27 (d, J =4.8 Hz, 1H), 8.18-8.08 (m, 3H), 8.07-8.00 (m, 2H), 7.78 (s, 1H), 7.71(t, J = 6.4 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.04-6.96(m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 5.33 (dd, J = 4.8, 12.4 Hz, 1H),4.31-4.21 (m, 2H), 3.62-3.57 (m, 4H), 3.55- 3.10 (m, 2H), 3.50-3.45 (m,2H), 3.41 (t, J = 6.4 Hz, 2H), 3.32 (s, 3H), 2.96- 2.84 (m, 1H),2.70-2.58 (m, 4H), 2.04-1.97 (m, 1H), 1.85-1.76 (m, 2H) 244 I-249 HQ CN902.4 11.08 (s, 1H), 11.03 (s, 1H), 9.03 (d, J = 4.8 Hz, 2H), 8.66 (t, J= 5.2 Hz, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 8.09-8.01 (m,4H), 7.78 (s, 1H), 7.71 (t, J = 6.4 Hz, 1H), 7.28 (s, 1H), 7.19 (d, J =5.2 Hz, 1H), 6.96-6.91 (m, 2H), 6.87-6.82 (m, 1H), 5.36 (dd, J = 5.2,12.5 Hz, 1H), 4.31-4.21 (m, 2H), 3.60-3.45 (m, 13H), 2.97-2.84 (m, 3H),2.65-2.55 (m, 2H), 2.03-1.96 (m, 1H), 1.84-1.77 (m, 2H) 245 I-250 HR FX936.2 11.10 (s, 1H), 10.06 (s, 1H), 8.99 (s, 1H), 8.92 (s, 1H), 8.65 (s,1H), 8.16 (d, J = 5.2 Hz, 1H), 8.04-8.00 (m, 2H), 7.99-7.94 (m, 2H),7.61-7.53 (m, 1H), 7.46-7.17 (m, 1H), 7.15-7.08 (m, 3H), 7.06-7.00 (m,2H), 6.59 (s, 1H), 5.09-5.03 (m, 1H), 3.77-3.72 (m, 1H), 3.64-3.45 (m,6H), 3.30- 3.26 (m, 6H), 3.22-3.12 (m, 2H), 2.87- 2.81 (m, 2H),2.75-2.69 (m, 1H), 2.61-2.58 (m, 1H), 2.56-2.55 (m, 1H), 2.10-1.97 (m,2H), 1.92-1.79 (m, 1H), 1.12-1.00 (m, 1H), 0.48- 0.43 (m, 2H), 0.25-0.20(m, 2H) 246 I-251 GV FX 853.6 11.10 (s, 1H), 10.05 (s, 1H), 8.99 (s,1H), 8.92 (s, 1H), 8.62 (t, J = 5.2 Hz, 1H), 8.17 (d, J = 5.2 Hz, 1H),8.06- 7.95 (m, 4H), 7.32 (s, 1H), 7.28-7.23 (m, 1H), 7.15-6.99 (m, 6H),5.38 (dd, J = 5.2, 12.8 Hz, 1H), 4.00 (t, J = 5.6 Hz, 2H), 3.69 (t, J =5.6 Hz, 2H), 3.59- 3.44 (m, 8H), 3.20-3.17 (m, 2H), 2.97- 2.83 (m, 1H),2.77-2.58 (m, 2H), 2.11- 1.93 (m, 1H), 1.18-0.98 (m, 1H), 0.54- 0.38 (m,2H), 0.30-0.16 (m, 2H) 247 I-252 HO FX 881.6 11.08 (s, 1H), 10.03 (s,1H), 8.99 (s, 1H), 8.92 (s, 1H), 8.65 (t, J = 5.2 Hz, 1H), 8.17 (d, J =5.6 Hz, 1H), 8.07- 8.01 (m, 2H), 8.00-7.94 (m, 2H), 7.47- 7.17 (m, 1H),7.15-7.07 (m, 2H), 7.07-7.04 (m, 1H), 7.03-6.96 (m, 2H), 6.89-6.81 (m,1H), 5.33 (dd, J = 5.6, 12.8 Hz, 1H), 3.61-3.55 (m, 4H), 3.54-3.50 (m,2H), 3.49-3.44 (m, 2H), 3.40 (t, J = 6.4 Hz, 2H), 3.31 (s, 3H), 3.19 (t,J = 6.0 Hz, 2H), 2.94- 2.85 (m, 1H), 2.65-2.61 (m, 4H), 2.03- 1.97 (m,1H), 1.83-1.76 (m, 2H), 1.12-1.04 (m, 1H), 0.50-0.41 (m, 2H), 0.28-0.19(m, 2H) 248 I-253 HQ FX 881.5 11.08 (s, 1H), 10.04 (s, 1H), 8.99 (s,1H), 8.90 (s, 1H), 8.65 (t, J = 5.6 Hz, 1H), 8.48 (s, 1H), 8.17 (d, J =5.2 Hz, 1H), 8.04-8.00 (m, 2H), 7.98-7.93 (m, 2H), 7.47-7.45 (m, 1H),7.46 (s, 1H), 7.34-7.31 (m, 1H), 7.14-7.08 (m, 2H), 7.05 (d, J = 1.2,5.3 Hz, 1H), 6.96-6.92 (m, 2H), 6.84 (dd, J = 2.8, 6.0 Hz, 1H), 5.36(dd, J = 5.2, 12.4 Hz, 1H), 3.61-3.57 (m, 4H), 3.55 (s, 5H), 3.49-3.43(m, 5H), 3.19 (t, J = 6.0 Hz, 2H), 2.96-2.90 (m, 3H), 2.69-2.66 (m, 2H),2.35-2.32 (m, 2H), 2.03- 1.94 (m, 1H), 1.85-1.76 (m, 2H), 1.12- 1.04 (m,1H), 0.49-0.43 (m, 2H), 0.26-0.21 (m, 2H) 249 I-254 HU OM 850.111.13-11.08 (m, 1H), 11.11 (s, 1H), 9.72 (s, 1H), 8.93 (s, 1H), 8.19 (s,1H), 8.16-8.12 (m, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.57 (dd, J = 7.2, 8.4Hz, 1H), 7.32-7.00 (m, 6H), 6.59 (t, J = 5.6 Hz, 1H), 5.05 (dd, J = 5.2,12.8 Hz, 1H), 4.32 (t, J = 5.2 Hz, 2H), 3.79 (t, J = 5.2 Hz, 2H), 3.59(t, J = 5.2 Hz, 2H), 3.54- 3.47 (m, 14H), 3.18 (t, J = 6.4 Hz, 2H),2.93-2.84 (m, 1H), 2.64-2.53 (m, 2H), 2.07-1.98 (m, 1H), 2.07- 1.98 (m,1H), 1.11-1.00 (m, 1H), 0.48- 0.43 (m, 2H), 0.25-0.20 (m, 2H)  250^(b)I-255 FU JL 723.0 11.20 (s, 1H), 10.14 (s, 1H), 9.08 (s, 1H), 8.92 (s,1H), 8.86 (d, J = 5.2 Hz, 2H), 8.62 (s, 1H), 8.09-7.93 (m, 7H), 7.78 (d,J = 2.0 Hz, 2H), 7.48-7.16 (m, 1H), 5.14 (dd, J = 5.2, 12.8 Hz, 1H),4.22 (s, 1H), 3.35 (d, J = 6.0 Hz, 2H), 3.16-3.12 (m, 1H), 2.98-2.83 (m,1H), 2.65-2.53 (m, 4H), 2.17- 2.01 (m, 1H), 1.97-1.89 (m, 1H) 251 I-256JG JE 896.6 11.19 (s, 1H), 10.02 (s, 1H), 9.00 (s, 1H), 8.91 (s, 1H),8.63 (t, J = 5.6 Hz, 1H), 8.26 (d, J = 5.6 Hz, 1H), 8.06- 8.00 (m, 2H),7.99-7.93 (m, 2H), 7.61 (t, J = 6.4 Hz, 1H), 7.46-7.18 (m, 3H),7.14-7.06 (m, 2H), 7.01-6.97 (m, 1H), 5.35 (dd, J = 5.2, 12.8 Hz, 1H),4.32-4.18 (m, 2H), 3.61-3.55 (m, 4H), 3.55-3.50 (m, 2H), 3.49- 3.41 (m,4H), 2.94-2.83 (m, 1H), 2.75- 2.70 (m, 2H), 2.69-2.66 (m, 1H), 2.57-2.53(m, 1H), 2.20-2.11 (m, 1H), 1.88-1.79 (m, 2H) 252 I-257 NK OM 786.410.88 (s, 1H), 9.47 (s, 1H), 8.69 (s, 1H), 8.00 (s, 1H), 7.98-7.94 (m,1H), 7.92 (d, J = 5.6 Hz, 1H), 7.57-7.54 (m, 2H), 7.06-6.82 (m, 3H),6.80- 7.80 (m, 1H), 4.91 (dd, J = 5.2, 12.8 Hz, 1H), 3.96-3.90 (m, 1H),3.54- 3.31 (m, 10H), 2.97-2.94 (m, 2H), 2.72-2.63 (m, 3H), 2.42-2.32 (m,2H), 1.93-1.81 (m, 2H), 1.71-1.63 (m, 3H), 0.87-0.80 (m, 1H), 0.26- 0.19(m, 2H), 0.02-0.03 (m, 2H) 253 I-258 NL OM 784.4 11.13 (s, 1H), 9.72 (s,1H), 8.93 (s, 1H), 8.19 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.80-7.70 (m,3H), 7.31-7.04 (m, 3H), 7.03-7.00 (m, 1H), 5.13 (dd, J = 5.2, 12.8 Hz,1H), 4.26-4.17 (m, 1H), 3.17 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 7.6 Hz,2H), 2.96-2.91 (m, 2H), 2.91-2.83 (m, 1H), 2.64-2.54 (m, 1H), 2.53-2.51(m, 1H), 2.33-2.27 (m, 2H), 2.10-1.89 (m, 7H), 1.69- 1.58 (m, 2H),1.53-1.44 (m, 2H), 1.39- 1.31 (m, 2H), 1.10-1.02 (m, 1H), 0.47-0.42 (m,2H), 0.24-0.20 (m, 2H) 254 I-259 NN OM 756.4 11.08 (s, 1H), 9.68 (s,1H), 8.89 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H),7.78-7.67 (m, 3H), 7.28-7.10 (m, 1H), 7.09-7.03 (m, 2H), 7.00-6.97 (m,1H), 5.11 (dd, J = 5.6, 12.8 Hz, 1H), 4.19 (t, J = 11.2 Hz, 1H),3.17-3.12 (m, 3H), 3.05 (t, J = 7.6 Hz, 2H), 2.96-2.82 (m, 3H), 2.65-2.63 (m, 1H), 2.56-2.51 (m, 1H), 2.35-2.29 (m, 3H), 2.02-1.93 (m, 5H),1.81-1.73 (m, 2H), 1.03 (t, J = 6.8 Hz, 1H), 0.45-0.39 (m, 2H), 0.21-0.16 (m, 2H)  255^(b) I-260 JI JL 723.3 11.10 (s, 1H), 10.14 (s, 1H),9.06 (s, 1H), 8.91 (s, 1H), 8.84 (d, J = 5.6 Hz, 2H), 8.58 (s, 1H), 7.98(s, 6H), 7.87- 7.81 (m, 2H), 7.79-7.73 (m, 1H), 7.47- 7.16 (m, 1H), 5.13(dd, J = 5.2, 12.8 Hz, 1H), 2.87 (t, J = 7.2 Hz, 3H), 2.65- 2.52 (m,4H), 2.09-2.00 (m, 1H), 1.99-1.88 (m, 2H) 256 I-261 OK JE 909.3 10.26(s, 1H), 9.22 (s, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.78 (t, J = 5.6 Hz,1H), 7.44 (d, J = 5.2 Hz, 1H), 7.23- 7.12 (m, 4H), 6.83-6.71 (m, 2H),6.65- 6.36 (m, 3H), 6.30 (d, J = 8.8 Hz, 1H), 6.21 (d, J = 7.2 Hz, 1H),5.78 (t, J = 5.6 Hz, 1H), 4.24 (dd, J = 5.2, 12.8 Hz, 1H), 3.49-3.38 (m,2H), 2.84- 2.80 (m, 2H), 2.80-2.74 (m, 6H), 2.63 (q, J = 5.2 Hz, 4H),2.15-2.00 (m, 1H), 1.81-1.72 (m, 2H), 1.25-1.18 (m, 1H) 257 I-262 JQ OM786.4 11.11 (s, 1H), 9.72 (s, 1H), 8.91 (s, 1H), 8.18 (s, 1H), 8.14 (d,J = 5.2 Hz, 1H), 7.87-7.83 (m, 2H), 7.79-7.75 (m, 1H), 7.30-7.11 (m,1H), 7.11- 7.06 (m, 2H), 7.03-6.99 (m, 1H), 5.19 5.11 (m, 1H), 4.20-4.13(m, 1H), 3.83- 3.60 (m, 2H), 3.20-3.14 (m, 2H), 3.06-3.00 (m, 2H),2.96-2.90 (m, 2H), 2.89-2.82 (m, 1H), 2.63-2.57 (m, 1H), 2.57-2.54 (m,1H), 2.54- 2.51 (m, 4H), 2.15-2.08 (m, 2H), 2.04- 1.98 (m, 1H),1.96-1.86 (m, 4H), 1.10-1.02 (m, 1H), 0.48-0.42 (m, 2H), 0.26-0.18 (m,2H) 258 I-263 NP OM 784.5 11.12 (s, 1H), 10.36 (s, 1H), 9.87 (s, 1H),9.02 (s, 1H), 8.24 (s, 1H), 8.15- 8.13 (m, 1H), 7.87 (d, J = 7.6 Hz,1H), 7.82 (s, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.39-7.08(m, 3H), 5.15 (dd,J = 52, 12.8 Hz, 1H), 4.64-4.53 (m, 1H), 3.67-3.59 (m, 2H), 3.27-3.25(m, 2H), 3.12-3.02 (m, 4H), 2.96-2.79 (m, 3H), 2.70-2.58 (m, 2H), 2.40-2.24 (m, 4H), 2.10-2.02 (m, 1H), 1.82- 1.65 (m, 4H), 1.39-1.30 (m, 2H),1.14-1.05 (m, 1H), 0.53-0.47 (m, 2H), 0.30-0.24 (m, 2H) 259 I-264 NR OM756.4 11.10 (s, 1H), 9.69 (s, 1H), 8.92 (s, 1H), 8.24-8.17 (m, 1H),8.16-8.12 (m, 1H), 7.89-7.80 (m, 2H), 7.76- 7.73 (m, 1H), 7.33-6.97 (m,4H), 5.14 (dd, J = 5.2, 12.8 Hz, 1H), 4.29-4.17 (m, 1H), 3.18 (t, J =6.0 Hz, 2H), 3.00- 2.91 (m, 2H), 2.91-2.79 (m, 3H), 2.65-2.55 (m, 2H),2.37-2.29 (m, 2H), 2.14-1.90 (m, 7H), 1.87-1.73 (m, 2H), 1.10-1.01 (m,1H), 0.53- 0.40 (m, 2H), 0.30-0.16 (m, 2H) 260 I-265 JG FX 868.4 11.18(s, 1H), 10.02 (s, 1H), 8.97 (s, 1H), 8.90 (s, 1H), 8.63 (t, J = 5.6 Hz,1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05- 7.99 (m, 2H), 7.98-7.92 (m, 2H),7.46- 7.17 (m, 1H), 7.15-7.02 (m, 5H), 7.01-6.96 (m, 1H), 5.34 (dd, J =5.2, 12.8 Hz, 1H), 3.61-3.55 (m, 4H), 3.54- 3.51 (m, 2H), 3.47-3.42 (m,4H), 3.19 (t, J = 6.0 Hz, 2H), 2.92-2.82 (m, 1H), 2.74-2.69 (m, 2H),2.53-2.52 (m, 2H), 2.19-2.10 (m, 1H), 1.88- 1.79 (m, 2H), 1.12-1.01 (m,1H), 0.49- 0.41 (m, 2H), 0.25-0.19 (m, 2H) 261 I-266 JG CN 889.4 11.18(s, 1H), 11.02 (s, 1H), 9.03 (d, J = 2.8 Hz, 2H), 8.64 (t, J = 6.0 Hz,1H), 8.27 (d, J = 5.2 Hz, 1H), 8.14-8.00 (m, 5H), 7.81-7.66 (m, 2H),7.28 (s, 1H), 7.22-7.16 (m, 1H), 7.14-7.06 (m, 2H), 6.99 (d, J = 7.2 Hz,1H), 5.35 (dd, J = 5.6, 12.8 Hz, 1H), 4.35-4.14 (m, 2H), 3.60-3.57 (m,4H), 3.56- 3.51 (m, 2H), 3.50-3.41 (m, 4H), 2.91-2.81 (m, 1H), 2.76-2.65(m, 4H), 2.19-2.12 (m, 1H), 1.89-1.78 (m, 2H) 262 I-267 KK FX 964.211.08 (s, 1H), 10.00 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 8.65-8.60 (m,1H), 8.29 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 8.06-8.02 (m, 2H),8.00-7.96 (m, 2H), 7.59-7.54 (m, 1H), 7.46-7.17 (m, 1H), 7.15-7.11 (m,2H), 7.10- 7.01 (m, 4H), 6.22 (d, J = 8.0 Hz, 1H), 5.05 (J = 5.2, 12.8Hz, 1H), 3.58-3.51 (m, 10H), 3.45 (d, J = 5.6 Hz, 3H), 3.22-3.18 (m,2H), 2.77 (d, J = 11.6 Hz, 2H), 2.63-2.55 (m, 2H), 2.19 (t, J = 10.4 Hz,2H), 2.07-1.99 (m, 1H), 1.90 (d, J = 10.4 Hz, 2H), 1.51-1.43 (m, 2H),1.12-1.04 (m, 1H), 0.48- 0.45 (m, 2H), 0.26-0.21 (m, 2H) 263 I-268 NU FX920.0 10.85 (s, 1H), 9.78 (s, 1H), 8.74 (s, 1H), 8.67 (s, 1H), 8.39 (t,J = 5.4 Hz, 1H), 7.98 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.82-7.77 (m,2H), 7.76-7.72 (m, 2H), 7.34-7.26 (m, 1H), 7.23- 6.93 (m, 1H), 6.90-6.72(m, 6H), 5.98 (d, J = 8.2 Hz, 1H), 4.81 (dd, J = 5.6, 12.8 Hz, 1H),3.35-3.28 (m, 5H), 3.25- 3.18 (m, 2H), 2.95 (t, J = 6.0 Hz, 2H),2.69-2.54 (m, 3H), 2.36-2.29 (m, 3H), 2.01 (t, J = 10.4 Hz, 3H), 1.84-1.74 (m, 1H), 1.64 (d, J = 10.4 Hz, 2H), 1.29-1.18 (m, 2H), 0.91-0.79(m, 1H), 0.28-0.19 (m, 2H), 0.03- 0.04 (m, 2H) 264 I-269 JY FX 1008.711.07 (s, 1H), 10.00 (s, 1H), 8.96 (s, 1H), 8.92 (s, 1H), 8.64-8.58 (m,1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05-8.00 (m, 2H), 7.99-7.95 (m, 2H),7.59- 7.53 (m, 1H), 7.45-7.17 (m, 1H), 7.15- 7.11 (m, 2H), 7.15-7.10 (m,1H), 7.04-7.01 (m, 2H), 6.25-6.19 (m, 1H), 5.08-4.99 (m, 1H), 3.56-3.50(m, 15H), 3.21-3.14 (m, 2H), 2.90- 2.83 (m, 1H), 2.79-2.73 (m, 2H),2.62- 2.57 (m, 1H), 2.57-2.53 (m, 1H), 2.45-2.43 (m, 2H), 2.21-2.15 (m,2H), 2.05-1.98 (m, 1H), 1.92-1.86 (m, 2H), 1.51-1.42 (m, 2H), 1.10- 1.04(m, 1H), 0.47-0.43 (m, 2H), 0.24- 0.21 (m, 2H) 265 I-270 HZ FX 964.511.04 (s, 1H), 10.00 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 8.63 (t, J =5.6 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05- 7.96 (m, 4H), 7.53 (d, J =8.4 Hz, 1H), 7.46-7.16 (m, 1H), 7.12 (s, 1H), 7.07 (t, J = 5.6 Hz, 1H),7.04 (dd, J = 1.2, 5.2 Hz, 1H), 6.99-6.93 (m, 2H), 6.85 (dd, J = 1.6,8.8 Hz, 1H), 5.01 (dd, J = 5.6, 12.8 Hz, 1H), 3.62-3.36 (m, 13H), 3.19(t, J = 6.0 Hz, 2H), 2.92- 2.80 (m, 3H), 2.61-2.53 (m, 2H), 2.14 (t, J =10.8 Hz, 2H), 2.03-1.94 (m, 1H), 1.87 (d, J = 11.2 Hz, 2H), 1.45- 1.35(m, 2H), 1.11-1.03 (m, 1H), 0.50- 0.41 (m, 2H), 0.26-0.19 (m, 2H) 266I-271 JZ FX 920.5 11.03 (s, 1H), 9.99 (s, 1H), 8.97 (s, 1H), 8.90 (s,1H), 8.62 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05- 8.00 (m,2H), 7.99-7.95 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.45-7.16 (m, 1H),7.12 (s, 1H), 7.09-7.05 (m, 1H), 7.04 (d, J = 6, 4 Hz, 1H), 6.98-6.93(m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 5.06-4.96 (m, 1H), 3.58-3.52 (m, 4H),3.48-3.38 (m, 5H), 3.21-3.15 (m, 2H), 2.91- 2.81 (m, 3H), 2.64-2.54 (m,1H), 2.53- 2.52 (m, 1H), 2.20-2.12 (m, 2H), 2.03-1.95 (m, 1H), 1.90-1.82(m, 2H), 1.44-1.34 (m, 2H), 1.11-1.00 (m, 1H), 0.48-0.43 (m, 2H), 0.25-0.20 (m, 2H) 267 I-272 KA FX 1008.7 11.04 (s, 1H), 10.01 (s, 1H), 8.97(s, 1H), 8.92 (s, 1H), 8.62 (t, J = 5.2 Hz, 1H), 8.16 (d, J = 5.2 Hz,1H), 8.04- 7.96 (m, 4H), 7.53 (d, J = 8.4 Hz, 1H), 7.45-7.17 (m, 1H),7.11 (s, 1H), 7.07 (t, J = 5.6 Hz, 1H), 7.04 (d, J = 5.6 Hz, 1H),6.99-6.93 (m, 2H), 6.88-6.83 (m, 1H), 5.01 (dd, J = 5.2, 12.8 Hz, 1H),3.52-3.43 (m, 14H), 3.19 (t, J = 6.0 Hz, 2H), 2.92-2.81 (m, 3H), 2.58-2.61 (m, 1H), 2.57-2.54 (m, 2H), 2.46-2.44 (m, 2H), 2.13 (t, J = 10.8Hz, 2H), 2.01-1.94 (m, 1H), 1.91- 1.83 (m, 2H), 1.46-1.35 (m, 2H), 1.11-1.03 (m, 1H), 0.48-0.43 (m, 2H), 0.25-0.20 (m, 2H) 268 I-273 KL FX 950.511.06 (s, 1H), 10.00 (s, 1H), 8.97 (s, 1H), 8.90 (s, 1H), 8.62 (t, J =5.6 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.06- 7.94 (m, 4H), 7.66 (dd, J =7.2, 8.4 Hz, 1H), 7.46-7.16 (m, 3H), 7.12 (s, 1H), 7.07 (t, J = 5.2 Hz,1H), 7.04 (dd, J = 1.2, 5.2 Hz, 1H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H),3.59-3.53 (m, 8H), 3.48- 3.41 (m, 2H), 3.27-3.22 (m, 4H), 3.19 (t, J =6.0 Hz, 2H), 2.90-2.81 (m, 1H), 2.62-2.57 (m, 4H), 2.57-2.54 (m, 2H),2.54-2.52 (m, 2H), 2.08- 1.97 (m, 1H), 1.12-1.01 (m, 1H), 0.49- 0.41 (m,2H), 0.25-0.20 (m, 2H) 269 I-274 NY FX 906.4 11.07 (s, 1H), 10.02 (s,1H), 8.99 (s, 1H), 8.91 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 8.27 (s, 1H),8.17 (d, J = 5.2 Hz, 1H), 8.09-8.02 (m, 2H), 8.01-7.94 (m, 2H),7.69-7.61 (m, 1H), 7.33 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H),7.20-7.11 (m, 1H), 7.10-7.02 (m, 2H), 5.08 (dd, J = 5.6, 12.8 Hz, 1H),3.62-3.55 (m, 8H), 3.21 (d, J = 6.0 Hz, 4H), 2.93-2.82 (m, 2H), 2.64-2.57 (m, 6H), 2.07-1.98 (m, 1H), 1.12-1.04 (m, 1H), 0.50-0.43 (m, 2H),0.24 (q, J = 4.8 Hz, 2H) 270 I-275 KB FX 994.6 10.84 (s, 1H), 9.77 (s,1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.38 (t, J = 5.6 Hz, 1H), 7.93 (d, J =5.2 Hz, 1H), 7.85- 7.68 (m, 4H), 7.53-7.32 (m, 1H), 7.24- 6.92 (m, 3H),6.91-6.74 (m, 3H), 4.85 (dd, J = 5.6, 12.8 Hz, 1H), 3.37- 3.17 (m, 15H),3.03 (s, 4H), 2.95 (t, J = 6.0 Hz, 2H), 2.72-2.56 (m, 1H), 2.36 (d, J =4.4 Hz, 5H), 2.24-2.20 (m, 2H), 2.20-1.84 (m, 1H), 1.83- 1.74 (m, 1H),0.96-0.71 (m, 1H), 0.27- 0.15 (m, 2H), 0.05-0.07 (m, 2H) 271 I-276 OA FX950.5 10.85 (s, 1H), 9.81 (s, 1H), 8.75 (s, 1H), 8.68 (s, 1H), 8.42 (t,J = 5.6 Hz, 1H), 8.06 (s, 1H), 7.93 (d, J = 5.6 Hz, 1H), 7.84-7.70 (m,4H), 7.42 (d, J = 8.8 Hz, 1H), 7.25-6.93 (m, 3H), 6.91- 6.83 (m, 2H),6.81 (dd, J = 1.2, 5.2 Hz, 1H), 4.83 (dd, J = 5.2, 12.8 Hz, 1H),3.40-3.29 (m, 8H), 3.26-3.19 (m, 2H), 3.15 (s, 4H), 2.95 (t, J = 6.0 Hz,2H), 2.71-2.58 (m, 1H), 2.36 (s, 2H), 2.31-2.29 (m, 6H), 1.84-1.70 (m,1H), 0.85-0.81 (m, 1H), 0.28- 0.14 (m, 2H), 0.03-0.15 (m, 2H) 272 I-277KF FX 906.4 11.06 (s, 1H), 10.00 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H),8.63 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 8.8 Hz,2H), 7.99 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.46- 7.15 (m,3H), 7.12 (s, 1H), 7.11-7.01 (m, 2H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H),3.61-3.53 (m, 4H), 3.50-3.44 (m, 2H), 3.39-3.34 (m, 4H), 3.19 (t, J =6.0 Hz, 2H), 2.95-2.81 (m, 1H), 2.61-2.53 (m, 8H), 2.06-1.95 (m, 1H),1.12-1.01 (m, 1H), 0.51-0.42 (m, 2H), 0.28-0.18 (m, 2H) 273 I-278 NZ FX994.5 11.07 (s, 2H), 10.21 (s, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 8.68 (t,J = 5.2 Hz, 1H), 8.13-7.92 (m, 5H), 7.73 (d, J = 8.4 Hz, 1H), 7.65 (s,1H), 7.50-7.18 (m, 4H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 4.19 (d, J =13.6 Hz, 2H), 3.90- 3.78 (m, 2H), 3.62-3.52 (m, 12H), 3.50-3.29 (m, 8H),3.19-3.17 (m, 2H), 2.95-2.80 (m, 1H), 2.69-2.53 (m, 2H), 2.08-1.96 (m,1H), 1.23- 1.09 (m, 1H), 0.61-0.51 (m, 2H), 0.35- 0.31 (m, 2H) 274 I-279GD JE 922.1 11.09 (s, 1H), 10.01 (s, 1H), 9.00 (s, 1H), 8.86 (s, 1H),8.25 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 6.4 Hz, 2H), 7.80 (d, J = 7.2 Hz,1H), 7.74 (s, 1H), 7.68 (s, 1H), 7.63-7.53 (m, 3H), 7.45-7.14 (m, 3H),5.12 (dd, J = 5.2, 12.8 Hz, 1H), 4.31-4.18 (m, 2H), 3.66-3.38 (m, 10H),3.00 (s, 3H), 2.93-2.76 (m, 3H), 2.64-2.52 (m, 2H), 2.09-1.99 (m, 1H),1.85 (t, J = 7.2 Hz, 2H) 275 I-280 HQ JE 909.5 11.07 (s, 1H), 10.03 (s,1H), 9.00 (s, 1H), 8.93-8.89 (m, 1H), 8.66-8.61 (m, 1H), 8.25 (d, J =5.2 Hz, 1H), 8.03- 7.94 (m, 4H), 7.61 (t, J = 6.4 Hz, 1H), 7.46-7.18 (m,3H), 7.08-6.75 (m, 3H), 5.41-5.30 (m, 1H), 4.30- 4.20 (m, 2H), 3.62-3.43(m, 13H), 2.98-2.81 (m, 3H), 2.66-2.53 (m, 2H), 2.03-1.95 (m, 1H),1.86-1.75 (m, 2H) 276 I-281 HR JE 964.4 11.11 (s, 1H), 10.07 (s, 1H),9.02 (s, 1H), 8.93 (s, 1H), 8.65 (s, 1H), 8.26 (d, J = 5.2 Hz, 1H),8.06-8.00 (m, 2H), 8.00-7.94 (m, 2H), 7.63 (t, J = 6.4 Hz, 1H), 7.57 (t,J = 8.0 Hz, 1H), 7.54- 7.30 (m, 1H), 7.27 (s, 1H), 7.22 (d, J = 5.2 Hz,1H), 7.14 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.60 (s, 1H),5.11-5.01 (m, 1H), 4.32-4.21 (m, 2H), 3.80-3.70 (m, 1H), 3.59- 3.45 (m,10H), 2.95-2.87 (m, 1H), 2.87-2.72 (m, 2H), 2.71-2.63 (m, 1H), 2.63-2.57(m, 1H), 2.56-2.53 (m, 2H), 2.13-1.99 (m, 2H), 1.92-1.80 (m, 1H) 277I-282 HK JE 964.1 11.08 (s, 1H), 10.03 (s, 1H), 9.01 (s, 1H), 8.92 (s,1H), 8.62 (t, J = 5.6 Hz, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.06- 8.00 (m,2H), 8.00-7.94 (m, 2H), 7.64- 7.55 (m, 2H), 7.47-7.17 (m, 3H), 7.13 (d,J = 8.8 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 6.59 (t, J = 6.0 Hz, 1H),5.09-5.03 (m, 1H), 4.31-4.20 (m, 2H), 3.80-3.72 (m, 1H), 3.65-3.54 (m,6H), 3.50-3.42 (m, 4H), 3.31 (t, J = 5.6 Hz, 2H), 2.94-2.86 (m, 1H),2.85-2.81 (m, 1H), 2.75-2.68 (m, 1H), 2.62-2.54 (m, 2H), 2.12-1.99 (m,2H), 1.87 (t, J = 10.4 Hz, 1H) 278 I-283 KK JE 992.5 11.09 (s, 1H),10.02 (s, 1H), 9.00 (s, 1H), 8.92 (s, 1H), 8.63 (t, J = 52 Hz, 1H), 8.26(d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 8.06-7.96 (m, 4H), 7.64-7.53 (m, 2H),7.27 (s, 1H), 7.46-7.25 (m, 1H), 7.24-7.20 (m, 1H), 7.13 (d, J = 8.8 Hz,1H), 7.03 (d, J = 7.2 Hz, 1H), 6.22 (d, J = 8.0 Hz, 1H), 5.05 (dd, J =5.6, 12.8 Hz, 1H), 4.30-4.20 (m, 2H), 3.48-3.43 (m, 1H), 3.60-3.42 (m,1H), 2.95-2.74 (m, 3H), 2.63-2.52 (m, 5H), 2.21 (t, J = 10.4 Hz, 2H),2.07- 1.98 (m, 1H), 1.90 (d, J = 11.2 Hz, 2H), 1.47 (q, J = 10.0 Hz, 2H) 279^(b) I-284 KH OL 1152.1 11.10 (s, 1H), 10.10 (s, 1H), 9.14 (s, 1H),8.79 (s, 1H), 8.63 (t, J = 6.4 Hz, 1H), 8.10 (d, J = 6.4 Hz, 1H), 7.84-7.72 (m, 2H), 7.65-7.40 (m, 5H), 7.43-7.16 (m, 2H), 7.12-7.09 (m, 1H),7.03-7.01 (m, 1H), 6.59 (s, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H), 4.58(d, J = 9.6 Hz, 1H), 4.48-4.21 (m, 4H), 4.01-3.92 (m, 2H), 3.77-3.60 (m,15H), 3.35-3.30 (m, 2H), 2.96- 2.82 (m, 1H), 2.60-2.58 (m, 2H), 2.12-1.97 (m, 2H), 1.96-1.85 (m, 1H), 1.19-1.10 (m, 1H), 1.00-0.88 (m, 9H),0.59-0.56 (m, 2H), 0.34-0.32 (m, 2H)  280^(b) I-285 OC OL 1193.810.86-10.84 (m, 1H), 10.85 (s, 1H), 9.76 (s, 1H), 8.80-8.74 (m, 1H),8.77 (s, 1H), 8.55 (s, 1H), 8.39 (t, J = 6.4 Hz, 1H), 7.90 (d, J = 4.8Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.34-7.29 (m, 1H), 7.24-7.19 (m, 3H),7.18-6.90 (m, 3H), 6.87 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 6.8 Hz, 1H),6.35 (t, J = 5.6 Hz, 1H), 5.03 (s, 1H), 4.81 (dd, J = 5.2, 12.8 Hz, 1H),4.27-4.14 (m, 3H), 4.08- 4.00 (m, 1H), 4.08-4.00 (m, 1H), 3.71 (m, 2H),3.68 (m, 1H), 3.63-3.56 (m, 1H), 3.38-3.33 (m, 10H), 3.21 (d, J = 5.2Hz, 2H), 2.97 (m, 2H), 2.70- 2.58 (m, 1H), 2.38-2.34 (m, 1H), 2.34- 2.30(m, 1H), 2.05-1.99 (m, 1H), 1.90-1.86 (m, 1H), 1.79 (m, 1H), 1.76 (s,3H), 1.77-1.74 (m, 1H), 0.90- 0.84 (m, 1H), 0.72 (s, 9H), 0.26 (m, 2H),0.04-−0.01 (m, 2H)  282^(b) I-287 KG OL 1160.5 11.09 (s, 1H), 10.09 (s,1H), 9.12 (s, (M + 23)⁺ 1H), 8.80 (s, 1H), 8.51 (t, J = 6.4 Hz, 1H),8.10 (d, J = 6.4 Hz, 1H), 7.86- 7.76 (m, 2H), 7.64-7.50 (m, 2H), 7.43(d, J = 8.4 Hz, 2H), 7.33-6.98 (m, 4H), 6.60 (s, 1H), 5.05 (dd, J = 5.2,13.2 Hz, 1H), 4.41-4.29 (m, 4H), 4.09 (s, 2H), 3.70-3.23 (m, 18H), 2.94-2.82 (m, 1H), 2.60-2.56 (m, 2H), 2.09- 1.97 (m, 2H), 1.92-1.82 (m, 1H),1.19-1.09 (m, 1H), 0.58-0.54 (m, 2H), 0.34-0.30 (m, 2H)  283^(b) I-288OB OL 1080.7 11.09 (s, 1H), 9.98 (s, 1H), 8.95 (s, 1H), 8.78 (s, 1H),8.58 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H),7.86-7.76 (m, 1H), 7.62-7.52 (m, 1H), 7.48-7.12 (m, 4H), 7.12- 6.98 (m,4H), 6.59 (s, 1H), 5.25 (s, 1H), 5.04 (d, J = 8.4 Hz, 1H), 4.44- 4.40(m, 1H), 4.36-4.62 (m, 2H), 4.12- 4.10 (m, 2H), 3.86-3.70 (m, 1H),3.65-3.51 (m, 14H), 3.19 (d, J = 6.0 Hz, 2H), 2.88-2.82 (m, 1H), 2.62-2.60 (m, 1H), 2.58-2.57 (m, 1H), 2.28- 2.22 (m, 1H), 2.10-2.04 (m, 1H),2.01 (s, 3H) 1.10-1.02 (m, 1H), 0.50- 0.40 (m, 2H), 0.25-0.21 (m, 2H)285 I-290 KK DF 957.6 11.11 (s, 1H), 11.04 (s, 1H), 9.17 (s, 1H), 9.02(s, 1H), 8.75-8.71 (m, 1H), 8.14 (s, 1H), 8.12-8.03 (m, 6H), 7.79 (s,1H), 7.66 (s, 1H), 7.63-7.56 (m, 1H), 7.27-7.19 (m, 2H), 7.10-7.03 (m,1H), 6.20 (d, J = 7.6 Hz, 1H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H), 3.83 (d,J = 4.0 Hz, 3H), 3.64-3.54 (m, 7H), 3.38- 3.32 (m, 5H), 3.28 (s, 3H),3.11 (d, J = 12.0 Hz, 1H), 2.93-2.85 (m, 1H), 2.70-2.55 (m, 3H), 2.14(d, J = 12.8 Hz, 2H), 2.08-1.98 (m, 2H), 1.87- 1.84 (m, 1H), 1.19-1.13(m, 1H), 0.60- 0.55 (m, 2H), 0.36-0.32 (m, 2H) 286 I-291 KP 2-[2-[2-[[2-860.4 11.1 (s, 1H), 10.3 (s, 1H), 9.88 (s, 1H), (2, 6-dioxo-3- 8.98 (s,1H), 8.37 (s, 1H), 8.22 (s, 1H), piperidyl)-1,3- 8.17 (d, J = 5.6 Hz,1H), 7.78 (d, J = dioxo-isoindolin- 8.8 Hz, 2H), 7.58 (t, J = 7.6 Hz,1H), 4-yl]amino]- 7.43 (d, J = 8.8 Hz, 2H), 7.16 (d, J = ethoxy]ethoxy]8.8 Hz, 1H), 7.14-7.08 (m, 2H), 7.05- acetic acid 7.01 (m, 2H),6.69-6.59 (m, 1H), (synthesized 5.10-5.00 (m, 1H), 4.13 (s, 2H), 3.75-via Steps 1-2 3.63 (m, 6H), 3.56-3.51 (m, 2H), of Example 160) 3.25-3.02(m, 2H), 2.93-2.86 (m, 1H), 2.63-2.59 (m, 1H), 2.59-2.56 (m, 1H),2.03-1.99 (m, 1H), 1.13-1.07 (m, 1H), 0.49-0.43 (m, 2H), 0.27-0.21 (m,2H) 287 I-292 4-[2-[2-[2-(2- KR 841.1 11.08 (s, 1H), 10.81 (s, 1H), 8.97(s, aminoethoxy)- 1H), 8.38 (s, 1H), 8.25 (d, J = 5.6 Hz,ethoxy]ethoxy]- 1H), 8.21 (s, 1H), 7.71-7.65 (m, 1H), ethylamino]- 7.56(t, J = 8.0 Hz, 1H), 7.25 (s, 1H), 2-(2,6-dioxo- 7.17 (d, J = 5.6 Hz,1H), 7.11 (d, J = 3-piperidyl)- 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H),isoindoline- 6.58 (s, 1H), 5.04 (dd, J = 5.6, 12.8 Hz, 1,3-dione 1H),4.33-4.17 (m, 2H), 3.93 (s, 3H), (synthesized 3.61 (t, J = 5.2 Hz, 2H),3.55 (d, J = via Steps 1-2 4.8 Hz, 10H), 3.46 (d, J = 4.8 Hz, 4H), ofExample 128) 2.91-2.83 (m, 1H), 2.60-2.56 (m, 1H), 2.56-2.52 (m, 1H),2.08-2.00-(m, 1H) 288 I-293 LP CW 1109.6 10.95 (s, 1H), 9.01-8.93 (m,2H), 8.60- 8.54 (m, 1H), 8.37-8.32 (s, 1H), 8.25-8.23 (m, 1H), 8.18 (s,1H), 7.89- 7.77 (m, 1H), 7.74-7.61 (m, 2H), 7.51 (s, 1H), 7.46-7.33 (m,4H), 7.25 (s, 1H), 7.16 (d, J = 5.2 Hz, 1H), 4.58- 4.18 (m, 7H),3.69-3.51 (m, 16H), 3.24-3.17 (m, 3H), 3.11-3.08 (m, 1H), 2.67-2.57 (m,1H), 2.47-2.41 (m, 4H), 2.25-2.17 (m, 1H), 2.13- 2.02 (m, 2H), 1.97-1.78(m, 4H), 1.68- 1.50 (m, 2H), 0.90 (s, 9H) 289 I-294 LR KR 839.4 11.08(s, 1H), 10.84 (s, 1H), 8.97 (s, 1H), 8.37 (s, 1H), 8.35 (t, J = 5.6 Hz,1H), 8.25 (d, J = 5.6 Hz, 1H), 7.68 (t, J = 6.4 Hz, 1H), 7.59-7.53 (m,1H), 7.25 (s, 1H), 7.17 (dd, J = 1.2, 5.2 Hz, 1H), 7.05 (d, J = 8.8 Hz,1H), 7.00 (d, J = 7.2 Hz, 1H), 6.63 (t, J = 5.6 Hz, 1H), 5.04 (dd, J =5.2, 12.8 Hz, 1H), 4.30-4.19 (m, 2H), 3.93 (s, 3H), 3.54- 3.39 (m, 12H),2.93-2.83 (m, 1H), 2.60 (d, J = 2.4 Hz, 1H), 2.58-2.54 (m, 1H),2.07-1.97 (m, 1H), 1.85- 1.73 (m, 6H) 290 I-295 LP KR 1020.1 10.82 (s,1H), 8.97 (d, J = 1.6 Hz, 2H), (M + Na)⁺ 8.57 (t, J = 6.0 Hz, 1H), 8.38(s, 1H), 8.27-8.22 (m, 2H), 7.70 (t, J = 6.4 Hz, 1H), 7.46-7.30 (m, 4H),7.25 (s, 1H), 7.17 (dd, J = 1.2, 5.2 Hz, 1H), 4.52 (t, J = 8.0 Hz, 1H),4.44-4.31 (m, 2H), 4.29-4.19 (m, 3H), 3.94 (s, 3H), 3.74- 3.52 (m, 14H),3.20 (d, J = 6.0 Hz, 2H), 3.08 (s, 1H), 2.61 (td, J = 6.0, 12.0 Hz, 1H),2.46-2.38 (m, 4H), 2.11- 1.99 (m, 1H), 1.95-1.80 (m, 1H), 0.90 (s, 9H)291 I-296 LX FX 1204.2 10.04 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.64(br t, J = 5.4 Hz, 1H), 8.20- 8.14 (m, 2H), 8.06-7.95 (m, 5H), 7.47-7.42 (m, 1H), 7.33-7.29 (m, 1H), 7.14-7.02 (m, 9H), 6.93 (d, J = 2.0 Hz,1H), 6.82-6.74 (m, 2H), 5.03 (d, J = 9.6 Hz, 1H), 4.93-4.85 (m, 2H),4.71-4.61 (m, 2H), 4.36 (t, J = 5.2 Hz, 4H), 4.14-4.03 (m, 3H), 3.85 (d,J = 9.2 Hz, 2H), 3.73 (t, J = 4.4 Hz, 3H), 3.46-3.43 (m, 8H), 3.20-3.16(m, 6H), 3.03-2.94 (m, 2H), 2.70-2.65 (m, 2H), 2.36-2.32 (m, 1H), 1.91-1.75 (m, 2H), 1.68 (d, J = 5.6 Hz, 1H), 1.62-1.50 (m, 2H), 1.04 (d, J =3.6 Hz, 9H), 0.49-0.43 (m, 2H), 0.26- 0.21 (m, 2H) 292 I-297 LZ KR 853.411.09 (s, 1H), 10.85 (s, 1H), 8.96 (s, 1H), 8.36 (s, 1H), 8.34-8.20 (m,2H), 7.71-7.66 (m, 1H), 7.25 (s, 1H), 7.17 (d, J = 4.4 Hz, 1H),6.99-6.86 (m, 2H), 6.86-6.76 (m, 1H), 5.42-5.28 (m, 1H), 4.31-4.18 (m,2H), 3.91 (s, 3H), 3.54 (s, 3H), 3.48-3.44 (m, 4H), 3.24-3.17 (m, 4H),2.97-2.85 (m, 3H), 2.73-2.63 (m, 2H), 2.62-2.55 (m, 2H), 2.02-1.97 (m,1H), 1.86- 1.72 (m, 4H), 0.90 (s, 6H)  293^(b) I-298 MD MC 1144.5 10.82(s, 1H), 8.99-8.96 (m, 2H), 8.61- 8.56 (m, 1H), 8.38 (s, 1H), 8.27- 8.22(m, 2H), 7.73-7.65 (m, 1H), 7.43- 7.37 (m, 5H), 7.25 (s, 1H), 7.18- 7.15(m, Hz, 1H), 5.16-5.12 (m, 1H), 4.55 (d, J = 9.6 Hz, 1H), 4.46-4.41 (m,1H), 4.36-4.32 (m, 1H), 4.27- 4.23 (m, 2H), 3.95 (s, 2H), 3.93 (s, 3H),3.70-3.40 (m, 26H), 2.53-2.52 (m, 1H), 2.45-2.41 (m, 4H), 2.06- 2.00 (m,1H), 1.93-1.85 (m, 1H), 0.95- 0.90 (m, 9H) 294 I-299 ME KR 1056.4 10.82(s, 1H), 8.98 (s, 2H), 8.59 (t, J = 5.6 Hz, 1H), 8.39 (s, 1H), 8.28-8.20(m, 2H), 7.69 (t, J = 6.4 Hz, 1H), 7.46- 7.36 (m, 5H), 7.26 (s, 1H),7.17 (d, J = 5.6 Hz, 1H), 5.16 (d, J = 3.2 Hz, 1H), 4.56 (d, J = 9.2 Hz,1H), 4.48- 4.42 (m, 1H), 4.42-4.31 (m, 2H), 4.30- 4.27 (m, 1H),4.26-4.19 (m, 2H), 3.96 (s, 2H), 3.94 (s, 3H), 3.70-3.43 (m, 16H),2.56-2.52 (m, 2H), 2.44 (s, 3H), 2.09-2.03 (m, 1H), 1.96-1.84 (m, 1H),0.94 (s, 9H)  295^(b) I-300 4-[2-[2-[2- MF 667.3 11.10 (s, 1H), 10.82(s, 1H), 8.82 (d, J = (2-aminoethoxy)- 0.8 Hz, 1H), 8.60 (d, J = 0.8 Hz,ethoxy]ethoxy] 1H), 8.33 (s, 1H), 8.21 (t, J = 5.6 Hz, ethylamino]- 1H),7.56 (dd, J = 7.2, 8.4 Hz, 1H), 2-(2,6-dioxo- 7.11 (d, J = 8.4 Hz, 1H),7.02 (d, J = 3-piperidyl)- 7.2 Hz, 1H), 6.59 (t, J = 5.6 Hz, 1H),isoindoline- 5.05 (dd, J = 5.2, 12.8 Hz, 1H), 3.91 (s, 1,3-dione 3H),3.63-3.57 (m, 2H), 3.57-3.49 (synthesized (m, 10H), 3.47-3.39 (m, 4H),2.93- via Steps 1-2 2.82 (m, 1H), 2.63-2.52 (m, 2H), 2.08- of Example128) 1.97 (m, 1H)  296^(b) I-301 4-[2-[2-[2- MI 744.1 11.08 (s, 1H),10.89 (s, 1H), 9.07 (s, (2-aminoethoxy)- 1H), 8.83 (d, J = 6.4 Hz, 2H),8.38 (s, ethoxy]ethoxy]- 1H), 8.25-8.22 (m, 1H), 7.94 (d, J =ethylamino]- 6.0 Hz, 2H), 7.57-7.53(m, 1H), 7.10 2-(2,6-dioxo- (d, J =8.8 Hz, 1H), 7.01 (d, J = 6.4 3-piperidyl)- Hz, 1H), 6.59-6.56 (m, 1H),5.07- isoindoline- 5.02 (m, 1H), 3.93 (s, 3H), 3.61-3.59 1,3-dione (m,2H), 3.55-3.54 (m, 10H), 3.46- (synthesized 3.43 (m, 4H), 2.87-2.86 (m,1H), 2.82- via Steps 1-2 2.56 (m, 2H), 2.04-2.01 (m, 1H) of Example 128)^(a)For variations on Method 12, see Table 10. ^(b)No deprotection Step2 was required.

Further Examples Using Synthetic Methods Similar to Method 12 Example281:[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-1-[(2S)-2-[[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]pyrrolidin-3-yl](2S)-pyrrolidine-2-carboxylate,I-286

To a solution of O1-benzyl02-[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-1-[(2S)-2-[[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate (140 mg, 101 umol, synthesized viaMethod 12 with Intermediate KJ as the amine and2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)aceticacid, syntheisized via Steps 1-2 of Example 152, as the acid in Step 1)in DCM (4 mL) was added HBr/HOAc (101 umol, 2 mL, 33% solution), and thereaction mixture was stirred at rt for 1.5 hr. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 21%-41%, 8min) to give the title compound (42.9 mg, 32% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) 11.07 (s, 1H), 9.95 (s, 1H), 8.96 (s, 1H),8.78 (s, 1H), 8.64 (t, J=6.0 Hz, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.85-7.71(m, 2H), 7.55 (t, J=−8.0 Hz, 1H), 7.48-7.14 (m, 4H), 7.14-7.09 (m, 2H),7.08-7.05 (m, 1H), 7.04-6.98 (m, 2H), 6.62-6.53 (m, 1H), 5.30 (s, 1H),5.04 (dd, J=5.2, 12.8 Hz, 1H), 4.54-4.35 (m, 3H), 4.32-4.24 (m, 1H),3.98-3.89 (m, 3H), 3.87-3.82 (m, 1H), 3.70-3.58 (m, 11H), 3.48-3.40 (m,2H), 3.19 (t, J=6.0 Hz, 2H), 2.93-2.83 (m, 2H), 2.80-2.72 (m, 1H),2.63-2.54 (m, 2H), 2.29-2.22 (m, 1H), 2.18-1.87 (m, 4H), 1.77-1.69 (m,1H), 1.68-1.53 (m, 1H), 1.09-1.02 (m, 1H), 1.00-0.90 (m, 9H), 0.49-0.41(m, 2H), 0.26-0.19 (m, 2H); LC-MS (ESI⁺) m/z 1248.3 (M+H)⁺.

Example 284:[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]]methylcarbamoyl]-1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetyl]pyrrolidin-3-yl](2S)-pyrrolidine-2-carboxylate,I-289

To a solution of O1-benzyl02-[(3R,5S)-5-[[4-[4-[[2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methylcarbamoyl]-1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]acetyl]pyrrolidin-3-yl](2S)-pyrrolidine-1,2-dicarboxylate(70 mg, 55.1 umol, synthesized via Step 1 of Method 12, coupling amineintermediate KI with2-(2-(2-(2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)acetic acid (synthesized via Steps 1-2 of Example 152) as theacid) in DCM (2 mL) was added HBr/AcOH (4 M, 1 mL, 33 wt %), and thereaction mixture was stirred at rt for 4 hrs. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B3%: 10%-37%, 2min) to give the title compound (40.7 mg, 61% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),9.95 (s, 1H), 8.96 (s, 1H), 8.79 (s, 1H), 8.57 (t, J=5.6 Hz, 1H), 8.16(d, J=5.2 Hz, 1H), 7.85-7.76 (m, 2H), 7.61-7.53 (m, 1H), 7.43 (d, J=8.4Hz, 2H), 7.41-7.09 (m, 3H), 7.09-6.97 (m, 3H), 6.64-6.52 (m, 1H), 5.29(s, 1H), 5.04 (dd, J=5.6, 12.8 Hz, 1H), 4.42 (t, J=7.6 Hz, 1H),4.38-4.30 (m, 2H), 4.14-4.03 (m, 2H), 3.85-3.64 (m, 4H), 3.63-3.59 (m,4H), 3.51-3.41 (m, 8H), 3.22-3.02 (m, 2H), 2.92-2.84 (m, 2H), 2.80-2.74(m, 1H), 2.64-2.55 (m, 2H), 2.27-2.20 (m, 1H), 2.15-2.06 (m, 1H),2.04-1.92 (m, 2H), 1.77-1.69 (m, 1H), 1.68-1.57 (m, 2H), 1.11-1.01 (m,1H), 0.49-0.42 (m, 2H), 0.23 (q, J=4.8 Hz, 2H); LC-MS (ESI⁺) m/z 1135.7(M+1)⁺.

Example 297:N-[3-carbamoyl-1-[4-[[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methoxymethyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-302

To a mixture ofN-[3-carbamoyl-1-[4-(morpholin-2-ylmethoxymethyl)phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(70.0 mg, 109.89 umol, HCl, synthesized via Steps 1-2 of Method 12coupling amine tert-butyl2-[[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]methoxymethyl]morpholine-4-carboxylate, Intermediate MK, and acid2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid, Intermediate CM, in Step 1) in MeCN (10 mL) was added NaHCO₃(36.93 mg, 439.55 umol). Then2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethanesulfonate (48.29 mg, 109.89 umol, synthesized via Steps 1-2 ofExample 184) was added into the mixture. The mixture was stirred at 80°C. for 12 hours. On completion, the reaction mixture was concentrated invacuo. The residue was purified by prep-HPLC (column: Phenomenex SynergiC18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 25%-42%, 6min) to give the title compound (42.0 mg, 35% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 11.00 (s, 1H), 9.02 (s, 1H),8.92 (s, 1H), 8.24 (s, 1H), 8.06-8.02 (m, 1H), 8.04 (s, 1H), 7.94 (d,J=8.4 Hz, 2H), 7.74-7.66 (m, 2H), 7.60-7.53 (m, 1H), 7.46 (d, J=8.4 Hz,2H), 7.26 (s, 1H), 7.19-7.10 (m, 2H), 7.02 (d, J=7.2 Hz, 1H), 6.59 (t,J=5.6 Hz, 1H), 5.09-5.01 (m, 1H), 4.51 (s, 2H), 4.29-4.18 (m, 2H),3.79-3.68 (m, 1H), 3.58 (d, J=5.6, 15.2 Hz, 9H), 3.39 (d, J=4.8 Hz, 4H),2.92-2.75 (m, 2H), 2.72-2.53 (m, 3H), 2.33 (td, J=1.8, 9.2 Hz, 1H),2.08-1.97 (m, 1H), 2.10-1.97 (m, 1H); LC-MS (ESI⁺) m/z 944.1 (M+H)⁺.

Example 298:N-[3-carbamoyl-1-[4-[[1-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2-piperidyl]methoxymethyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-303

To a mixture ofN-[3-carbamoyl-1-[4-(2-piperidylmethoxymethyl)phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide(70.0 mg, 110.2 umol, HCl, synthesized via Method 12 coupling aminetert-butyl2-[[4-(4-amino-3-carbamoyl-pyrazol-1-yl)phenyl]methoxymethyl]piperidine-1-carboxylate,Intermediate MM and acid2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylic acid, Intermediate CM in Step 1) in CH₃CN (10 mL)was added NaHCO₃ (37.0 mg, 441 umol). Then2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethylmethanesulfonate (48.4 mg, 110 umol, synthesized via Steps 1-2 ofExample 184) was added into the mixture. The mixture was stirred at 80°C. for 24 hrs. On completion, the reaction mixture was concentrated invacuo. The residue was purified by prep-HPLC (column: Phenomenex SynergiC18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 22%-42%, 7min) to give the title compound (32.8 mg, 30% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 11.00 (s, 1H), 9.03 (s, 1H),8.92 (s, 1H), 8.28-8.25 (m, 3H), 8.04 (s, 1H), 7.93 (d, J=8.4 Hz, 2H),7.74-7.66 (m, 2H), 7.59-7.53 (m, 1H), 7.46 (d, J=8.4 Hz, 2H), 7.28 (s,1H), 7.19 (d, J=4.0 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.02 (d, J=7.2 Hz,1H), 6.58 (s, 1H), 5.05 (dd, J=5.6, 12.8 Hz, 1H), 4.49 (s, 2H), 4.25(dd, J=6.0, 9.2 Hz, 2H), 3.60-3.55 (m, 6H), 3.51 (s, 7H), 2.87-2.85 (m,4H), 2.70-2.64 (m, 3H), 2.34-2.14 (m, 2H), 1.60 (s, 3H), 1.36-1.24 (m,1H). LC-MS (ESI⁺) m/z 942.2 (M+H)⁺.

Example 299:N-[3-carbamoyl-1-[[1-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]triazol-4-yl]methyl]pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide,I-304

Step 2—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[[1-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]triazol-4-yl]methyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of tert-butylN-[4-[4-[(3-carbamoyl-1-prop-2-ynyl-pyrazol-4-yl)carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(106 mg, 209 umol, synthesized via Step 1 of Method 12 coupling amine4-amino-1-prop-2-ynyl-pyrazole-3-carboxamide, Intermediate MT with acid2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid, synthesized via Steps 1-4 of Intermediate DF) and4-[2-[2-(2-azidoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(60.0 mg, 139 umol, Intermediate MS) in t-BuOH (5 mL) was added CuSO₄(4.6 mg, 28.8 umol, 4.42 uL) and sodium;(2R)-2-[(1S)-1,2-dihydroxyethyl]-4-hydroxy-5-oxo-2H-furan-3-olate (11.1mg, 55.8 umol) in H₂O (5 mL). The reaction mixture was stirred at 60° C.for 2 hours under nitrogen. On completion, the reaction mixture waspoured into brine (30 mL) and extracted with EA (3×50 mL). The combinedorganic layers were washed with brine (50 mL), dried with anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(140 mg, 99% yield) as a light yellow solid. LC-MS (ESI⁺) m/z 936.5(M+H)⁺.

Step3—N-[3-carbamoyl-1-[[1-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]triazol-4-yl]methyl]pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[[1-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]triazol-4-yl]methyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(140 mg, 150 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 10 mL). Thereaction mixture was stirred at rt for 1 hour. On completion, thereaction mixture was concentrated in vacuo and purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 18%-35%, 6 min). The purity of product was only85%. Then the impure product was purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.05%HCl)-ACN]; B %: 16%-36%, 7.8 min) to give the title compound (6.40 mg,5% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H),10.99 (s, 1H), 9.47 (s, 1H), 9.09 (s, 1H), 8.44 (s, 1H), 8.13 (s, 1H),8.06 (d, J=6.0 Hz, 1H), 7.81 (s, 1H), 7.63 (s, 1H), 7.58-7.50 (m, 2H),7.18-7.23 (m, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.99 (d, J=6.4 Hz, 1H), 6.54(s, 1H), 5.50 (s, 2H), 5.10-4.94 (m, 1H), 4.51 (t, J=4.8 Hz, 2H),3.93-3.66 (m, 2H), 3.55-3.52 (m, 6H), 3.45-3.28 (m, 4H), 2.90-2.78 (m,1H), 2.61-2.56 (m, 1H), 2.05-1.96 (m, 1H), 1.19-1.09 (m, 1H), 0.60-0.53(m, 2H), 0.36-0.29 (m, 2H). LC-MS (ESI⁺) m/z 836.1 (M+H)⁺.

Example 300: (Method 16)N-[3-carbamoyl-1-[4-[[[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-305

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[[[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a mixture of4-[2-[2-[2-(aminomethyl)morpholin-4-yl]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(60.0 mg, 120 umol, HCl salt, Intermediate EJ) in DCM (5 mL) was addedTEA (18.3 mg, 181 umol), HOAc (14.5 mg, 241 umol) and tert-butylN-[4-[4-[[3-carbamoyl-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(96.7 mg, 120 umol, Intermediate GY). The mixture was stirred for 30minutes, and then NaBH(OAc)₃ (51.2 mg, 241 umol) was added. The mixturewas then stirred rt for 16 hours. On completion, the reaction mixturewas quenched by addition water (0.4 mL), and then concentrated in vacuoto give the title compound (120 mg, 95% yield) as yellow solid. LC-MS(ESI⁺) m/z 1043.6 (M+H)⁺.

Step2—N-[3-carbamoyl-1-[4-[[[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[[4-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]morpholin-2-yl]methylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(120 mg, 115 umol) in DCM (4 mL) was added HCl/dioxane (4 M, 1.03 mL).The mixture was stirred at rt for 1 hour. On completion, the reactionmixture was concentrated in vacuo to give a residue. The residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]) to give the title compound (72.2mg, 63%˜ yield) as yellow solid, ¹H NMR (400 MHz, DMSO-d₆) (11.01 (s,1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.25 (d, J=5.2 Hz, 1H), 8.20 (s, 1H),8.06 (s, 1H), 7.91 (d, J 8.4 Hz, 2H), 7.73-7.69 (m 1H), 7.59-7.55 (m1H), 7.49 (d, J=8.4 Hz, 2H), 7.26 (s, 1H), 7.20-7.11 (m, 2H), 7.03 (d,J=6.8 Hz, 1H), 6.60 (t, J=5.6 Hz, 1H), 5.05 (dd, J=5.6, 12.8 Hz, 1H),4.33-4.19 (m, 2H), 3.78 (s, 2H), 3.72 (d, J=12 Hz, 2H), 3.59 (t, J=5.2Hz, 2H), 3.55 (t, J=6.0 Hz, 2H), 3.48-3.44(m, 3H), 2.89-2.77 (m, 2H)2.70 (d, J 12.4 Hz, in) 2.62-2.55 (m, 2H), 2.49-2.43 (m, 4H), 2.07-197(m, 2H), 1.80 (t, J=10.8 Hz, 1H); LC-MS (ESI⁺) m/z 943.1 (M+H)⁺.

TABLE 22 Compounds synthesized via Method 16 with the reductiveamination of various amines with aldehydes in Step 1. LCMS Step 1 Step 1(ES+) Ex- Intermediate Intermediate m/z #ª^(, e) I-# Amine Aldehyde (M +H)⁺ 1HNMR (400 MHz, DMSO-d6) δ 301 I-306 FR GY 941.6 11.09 (s, 1H),11.00 (s, 1H), 9.03 (s, 1H), 8.89 (s, 1H), 8.29-8.21 (m, 2H), 8.02 (s,1H), 7.87 (d, J = 8.0 Hz, 2H), 7.77-7.64 (m, 2H), 7.57-7.43 (m, 3H),7.28 (s, 1H), 7.19 (d, J = 5.6 Hz, 1H), 7.08 (m, 1H), 7.04-6.97 (m, 1H),6.60-6.51 (m, 1H), 5.06 (dd, J = 4.8, 13.2 Hz, 1H), 4.34-4.17 (m, 2H),3.76 (s, 2H), 3.62-3.47 (m, 5H), 3.42- 3.38 (m, 3H), 2.95-2.79 (m, 3H),2.72- 2.57 (m, 5H), 2.02 (m, 1H), 1.60 (m, 2H), 1.53-1.20 (m, 4H) 302I-307 FS HM 884.1 11.11 (s, 1H), 9.92 (s, 1H), 8.96 (s, 1H), 8.85 (s,1H), 8.19-8.11 (m, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.59-7.47 (m, 3H),7.14-6.97 (m, 5H), 6.75 (t, J = 5.2 Hz, 1H), 5.04 (dd, J = 5.2, 13.2 Hz,1H), 3.87 (s, 2H), 3.38-3.26 (m, 6H), 3.18 (t, J = 6.0 Hz, 2H), 2.93-2.85 (m, 1H), 2.84-2.79 (m, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.69-2.66 (m,2H), 2.57-2.52 (m, 2H), 2.05-1.95 (m, 1H), 1.11-1.00 (m, 1H), 0.48- 0.42(m, 2H), 0.25-0.19 (m, 2H) 303 I-308 GD GC 873.5 11.11 (s, 1H), 10.98(s, 1H), 8.98 (s, 1H), 8.88 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.01 (s,1H), 7.88 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 7.6 Hz, 1H), 7.75- 7.70 (m,2H), 7.67 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.16 (t, J =6.0 Hz, 1H), 7.12 (s, 1H), 7.00 (dd, J = 1.2, 5.2 Hz, 1H), 5.12 (dd, J =5.2, 12.8 Hz, 1H), 3.57-5.55 (m, 4H), 3.51- 5.50 (m, 4H), 3.39 (t, J =6.0 Hz, 2H), 3.19 (t, J = 6.0 Hz, 2H), 2.93-2.83 (m, 1H), 2.79 (t, J =7.6 Hz, 2H), 2.63- 2.55 (m, 2H), 2.54 (s, 2H), 2.19 (s, 3H), 2.09-1.99(m, 1H), 1.89-1.78 (m, 2H), 1.13-0.99 (m, 1H), 0.50- 0.39 (m, 2H),0.27-0.17 (m, 2H) 304 I-309 GD GE 804.4 11.14-11.11 (m, 1H), 11.09 (s,1H), 9.08 (s, 1H), 8.89 (s, 1H), 8.85 (d, J = 5.6 Hz, 2H), 8.29 (s, 1H),8.03 (s, 1H), 7.97 (d, J = 6.0 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 7.79(d, J = 7.6 Hz, 1H), 7.78-7.73 (m, 2H), 7.68 (d, J = 7.2 Hz, 1H), 7.46(d, J = 8.4 Hz, 2H), 5.13 (dd, J = 5.4, 12.8 Hz, 1H), 3.62-3.58 (m, 2H),2.93-2.86 (m, 1H), 2.80 (t, J = 7.2 Hz, 2H), 2.61 (s, 1H), 2.56 (d, J =5.6 Hz, 4H), 2.20 (s, 3H), 2.06 (dd, J = 5.2, 10.3 Hz, 1H), 1.89-1.80(m, 2H) 305 I-310 GD GF 880.5 11.1 (s, 1H), 9.98 (s, 1H), 8.97 (s, 1H),8.78 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.82-7.73 (m, 4H), 7.69 (d, J =7.2 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.42- 7.14 (m, 1H), 7.13-7.07 (m,2H), 7.04 (d, J = 5.2 Hz, 1H), 5.17-5.09 (m, 1H), 3.57-3.55 (m, 4H),3.52- 3.48 (m, 8H), 3.24-3.04 (m, 2H), 2.84- 2.80 (m, 1H), 2.63-2.58 (m,1H), 2.57-2.55 (m, 1H), 2.44-2.41 (m, 2H), 2.19 (s, 3H), 2.08-2.02 (m,1H), 1.87-1.81 (m, 2H), 1.11-1.03 (m, 1H), 0.50-0.43 (m, 2H), 0.25-0.20(m, 2H) 306 I-311 GH GC 857.5 10.99 (s, 1H), 8.99 (s, 1H), 8.93 (s, 1H),8.25 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.03 (s, 1H), 7.94 (d, J = 8.8Hz, 2H), 7.80-7.71 (m, 3H), 7.70-7.64 (m, 1H), 7.54 (d, J = 8.4 Hz, 2H),7.16 (t, J = 5.2 Hz, 1H), 7.12 (s, 1H), 7.00 (dd, J = 1.2, 5.2 Hz, 1H),5.12 (dd, J = 5.2, 12.8 Hz, 1H), 3.87 (d, J = 6.4 Hz, 1H), 3.38-3.36 (m,2H), 3.34-3.31 (m, 2H), 3.18 (t, J = 6.4 Hz, 2H), 3.06 (t, J = 7.2 Hz,2H), 2.93-2.83 (m, 1H), 2.64-2.52 (m, 6H), 2.09-2.00 (m, 1H), 1.88-1.78(m, 2H), 1.55- 1.43 (m, 4H), 1.38-1.27 (m, 2H), 1.11- 1.01 (m, 1H),0.49-0.42 (m, 2H), 0.26-0.20 (m, 2H) 307 I-312 GJ GC 871.2 11.13 (s,1H), 10.98 (s, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.16 (d, J = 5.2 Hz,1H), 8.03 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.79-7.68 (m, 3H),7.68-7.61 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.16 (t, J = 5.2 Hz, 1H),7.12 (s, 1H), 7.00 (dd, J = 1.2, 5.2 Hz, 1H), 5.12 (dd, J = 5.2, 12.8Hz, 1H), 3.55 (s, 2H), 3.36 (t, J = 6.4 Hz, 2H), 3.32 (t, J = 6.4 Hz,2H), 3.19 (t, J = 6.4 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 3.08-3.00 (m,1H), 2.95-2.81 (m, 1H), 2.64-2.53 (m, 2H), 2.37 (t, J = 7.2 Hz, 2H),2.16 (s, 3H), 2.10-2.00 (m, 1H), 1.88-1.76 (m, 2H), 1.52-1.43 (m, 4H),1.34- 1.24 (m, 2H), 1.12-1.03 (m, 1H), 0.49- 0.43 (m, 2H), 0.24-2.2 (m,2H) 308 I-313 GL GC 829.5 811.14 (s, 1H), 11.01 (s, 1H), 9.01 (s, 1H),8.92 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 8.05 (s, 1H), 7.91 (d, J = 8.4Hz, 2H), 7.79-7.68 (m, 4H), 7.47 (d, J = 8.4 Hz, 2H), 7.22-7.14 (m, 1H),7.13 (s, 1H), 7.01 (d, J = 5.2 Hz, 1H), 5.14 (dd, J = 5.2, 12.8 Hz, 1H),3.58 (s, 2H), 3.54-3.50 (m, 2H), 3.45-3.41 (m, 2H), 3.20 (t, J = 5.6 Hz,2H), 3.09 (t, J = 7.2 Hz, 2H), 2.93-2.86 (m, 1H), 2.65-2.61(m, 1H),2.59-2.57 (m, 1H), 2.48-2.42 (m, 2H), 2.20 (s, 3H), 2.10-2.01 (m, 1H),1.91-1.82 (m, 2H), 1.12-1.03 (m, 1H), 0.51- 0.42 (m, 2H), 0.28-0.20 (m,2H) 309 I-314 GN GC 827.5 11.12 (s, 1H), 10.99 (s, 1H), 8.98 (s, 1H),8.91 (s, 1H), 8.17-8.14 (m, 1H), 8.03 (s, 1H), 7.94-7.88 (m, 2H), 7.78-7.70 (m, 3H), 7.67- 7.64 (m, 1H), 7.48-7.43 (m, 2H), 7.18-7.13 (m, 1H),7.11 (s, 1H), 7.02-6.98 (m, 1H), 5.15-5.08 (m, 1H), 3.56 (s, 2H), 3.18(t, J = 6.0 Hz, 2H), 3.00 (t, J = 7.6 Hz, 2H), 2.93-2.83 (m, 1H),2.64-2.52 (m, 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.16 (s, 3H), 2.09-2.01 (m,1H), 1.65- 1.53 (m, 2H), 1.52-1.42 (m, 2H), 1.36- 1.25 (m, 4H),1.10-1.02 (m, 1H), 0.48-0.41 (m, 2H), 0.25-0.19 (m, 2H) 310 I-315 GO GP884.5 10.76 (s, 1H), 8.76 (s, 2H), 8.12 (s, 1H), 7.93 (d, J = 4.8 Hz,1H), 7.87 (s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.54 (m, 4H), 7.32 (m, 2H),6.93 (m, 1H), 6.88 (s, 1H), 6.77 (d, J = 4.8 Hz, 1H), 4.91- 4.87 (m,1H), 3.26-3.16 (m, 2H), 2.95 (t, J = 5.6 Hz, 3H), 2.88-2.77 (m, 2H),2.73-2.68 (m, 4H), 2.65-2.52 (m, 3H), 2.39-2.34 (m, 2H), 1.89- 1.77 (m,1H), 1.75-1.51 (m, 2H), 1.44- 1.34 (m, 2H), 1.24-1.08 (m, 4H), 0.84-0.82(m, 1H), 0.23-0.21 (m, 2H), 0.00-0.02 (m, 2H); 311 I-316 GS GC 869.610.89 (s, 1H), 9.82 (s, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 8.45-8.45 (m,1H), 7.93 (d, J = 5.2 Hz, 1H), 7.81-7.75 (m, 2H), 7.74-7.69 (m, 2H),7.53- 7.47 (m, 2H), 7.45-7.40 (m, 1H), 7.24- 6.94 (m, 1H), 6.91-6.85 (m,2H), 6.83-6.78 (m, 1H), 4.89 (dd, J = 5.6, 12.8 Hz, 1H), 3.37-3.20 (m,10H), 2.95 (t, J = 6.8 Hz, 2H), 2.79 (t, J = 7.2 Hz, 2H), 2.71-2.62 (m,1H), 2.41- 2.38 (m, 1H), 2.36-2.34 (m, 1H), 1.86- 1.76 (m, 1H),1.62-1.53 (m, 2H), 0.89-0.80 (m, 1H), 0.26-0.19 (m, 2H), 0.03-0.00 (m,2H) 312 I-317 GT GC 855.2 11.00 (s, 1H), 9.00 (s, 1H), 8.93 (s, 1H),8.28 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 8.04 (s, 1H), 7.93 (d, J = 8.8Hz, 2H), 7.79-7.71 (m, 3H), 7.71-7.67 (m, 1H), 7.52 (d, J = 8.8 Hz, 2H),7.17 (t, J = 5.6 Hz, 1H), 7.13 (s, 1H), 7.01 (dd, J = 1.6, 5.2 Hz, 1H),5.13 (dd, J = 5.6, 12.8 Hz, 1H), 3.81 (s, 2H), 3.20 (t, J = 6.0 Hz, 2H),3.06-2.98 (m, 2H), 2.96-2.81 (m, 1H), 2.65-2.52 (m, 4H), 2.09-2.03 (m,1H), 1.65-1.55 (m, 2H), 1.51-1.40 (m, 2H), 1.33- 1.23 (m, 10H),1.13-1.02 (m, 1H), 0.51-0.44 (m, 2H), 0.28-0.20 (m, 2H) 313 I-318 GU GY829.5 11.02 (s, 2H), 9.04 (s, 1H), 8.93 (s, 1H), 8.25 (d, J = 5.2 Hz,1H), 8.20 (s, 1H), 8.06 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.77-7.68 (m,2H), 7.58-7.56 (m, 1H), 7.53-7.44 (m, 4H), 7.26 (s, 1H), 7.17 (dd, J =1.2, 5.2 Hz, 1H), 5.14 (dd, J = 5.2, 13.6 Hz, 1H), 4.53- 4.41 (m, 1H),4.30 (d, J = 17.2 Hz, 1H), 4.26-4.22 (m, 2H), 3.81 (s, 2H), 3.47 (d, J =6.0 Hz,, 2H), 3.39 (d, J = 6.0 Hz, 2H), 2.96-2.87 (m, 1H), 2.75- 2.68(m, 4H), 2.62-2.53 (m, 2H), 2.03-1.95 (m, 1H), 1.90-1.82 (m, 2H) 314I-319 GV GC 832.5 11.00 (s, 2H), 9.07-8.85 (m, 2H), 8.23 (s, 1H), 8.16(d, J = 5.2 Hz, 1H), 8.05 (s, 1H), 7.92 (d, J = 8.0 Hz, 2H), 7.74 (s,1H), 7.50 (d, J = 8.0 Hz, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.17 (t, J =5.2 Hz, 1H), 7.14-6.98 (m, 5H), 5.37 (m, 1H), 4.04-3.94 (m, 2H), 3.82(s, 2H), 3.73- 3.63 (m, 8H), 3.20-3.15 (m, 2H), 2.96-2.81 (m, 1H),2.75-2.61 (m, 4H), 2.06-1.95 (m, 1H), 1.19-0.96 (m, 1H), 0.46-0.41 (m,2H), 0.23- 0.18 (m, 2H) 315 I-320 GW GY 843.4 11.13 (s, 1H), 11.01 (s,1H), 9.02 (s, 1H), 8.92 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H),8.04 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.81-7.65 (m, 5H), 7.51 (d, J =8.4 Hz, 2H), 7.26 (s, 1H), 7.17 (dd, J = 1.2, 5.6 Hz, 1H), 5.12 (dd, J =5.2, 12.8 Hz, 1H), 4.30-4.21 (m, 2H), 3.82 (s, 2H), 3.48 (t, J = 5.6 Hz,2H), 3.42 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H), 2.92-2.83 (m,1H), 2.75-2.67 (t, J = 5.6 Hz, 2H), 2.64-2.53 (m, 2H), 2.11-2.00 (m,1H), 1.92-1.80 (m, 2H) 316 I-321 GX GY 887.4 11.50 (s, 1H), 11.02 (s,1H), 9.04 (s, 1H), 8.90 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H),8.04 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.77-7.70 (m, 4H), 7.69-7.66 (m,1H), 7.49 (d, J = 8.8 Hz, 2H), 7.28 (s, 1H), 7.19 (dd, J = 1.2, 5.2 Hz,1H), 5.13 (dd, J = 5.2, 12.4 Hz, 1H), 4.31-4.21 (m, 2H), 3.79 (s, 2H),3.57-3.41 (m, 8H), 3.05 (t, J = 6.8 Hz, 2H), 2.94-2.84 (m, 1H),2.72-2.68 (m, 2H), 2.64-2.57 (m, 1H), 2.57-2.54 (m, 1H), 2.09-2.03 (m,1H), 1.87-1.79 (m, 2H) 317 I-322 HA GY 975.2 11.09 (s, 1H), 11.00 (s,1H), 9.02 (s, 1H), 8.91 (s, 1H), 8.29-8.24 (m, 2H), 8.03 (s, 1H), 7.91(d, J = 8.4 Hz, 2H), 7.77-7.67 (m, 5H), 7.49 (d, J = 8.8 Hz, 2H), 7.27(s, 1H), 7.18 (dd, J = 1.6, 5.2 Hz, 1H), 5.13 (dd, J = 5.6, 12.8 Hz,1H), 4.30-4.21 (m, 2H), 3.79 (s, 2H), 3.52-3.46 (m, 14H), 3.40 (t, J =6.4 Hz, 2H), 3.05 (t, J = 7.6 Hz, 2H), 2.95-2.83 (m, 1H), 2.68 (t, J =5.6 Hz, 2H), 2.60-2.52 (m, 2H), 2.10-2.03 (m, 1H), 1.86-1.79 (m, 2H) 318I-323 MN GY 971.5 11.00 (s, 1H), 9.02 (s, 1H), 8.91 (s, 1H), 8.26 (d, J= 5.6 Hz, 2H), 8.04 (s, 1H), 7.93-7.83 (m, 5H), 7.74-7.68 (m, 2H), 7.49(d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H), 5.15 (dd, J= 5.6, 12.8 Hz, 1H), 4.49 (s, 2H), 4.31-4.21 (m, 2H), 3.78 (s, 2H),3.75-3.68 (m, 3H), 3.61-3.57 (m, 3H), 3.53-3.48 (m, 9H), 2.96-2.84 (m,1H), 2.71-2.57 (m, 5H), 2.34 (s, 1H), 2.12-2.02 (m, 1H) 319 I-324 HB GC845.5 10.99 (s, 1H), 8.99 (s, 1H), 8.90 (s, 1H), 8.25 (s, 1H), 8.16 (d,J = 5.2 Hz, 1H), 8.03 (, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.72 (s, 1H),7.58-7.53 (t, J = 4.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.46- 7.39 (m,2H), 7.16 (t, J = 5.6 Hz, 1H), 7.12 (s, 1H), 7.00 (dd, J = 1.2, 5.2 Hz,1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.43 (d, J = 17.2 Hz, 1H), 4.29(d, J = 17.2 Hz, 1H), 3.81 (s, 2H), 3.54- 3.47 (m, 6H), 3.39 (t, J = 6.4Hz, 2H), 3.19 (t, J = 6.4 Hz, 2H), 2.98-2.86 (m, 1H), 2.75-2.63 (m, 4H),2.63-2.52 (m, 2H), 2.05-1.96 (m, 1H), 1.87- 1.77 (m, 2H), 1.13-1.02 (m,1H), 0.49- 0.41 (m, 2H), 0.26-0.20 (m, 2H) 320 I-325 HC GC 889.5 10.99(s, 1H), 8.99 (s, 1H), 8.91 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.04 (s,1H), 7.92 (s, 1H), 7.89 (s, 1H), 7.73 (s, 1H), 7.58-7.53 (m, 1H), 7.50(s, 1H), 7.48 (s, 1H), 7.44 (d, J = 4.4 Hz, 2H), 7.19-7.13 (m, 1H), 7.12(s, 1H), 7.02- 6.98 (m, 1H), 5.17-5.09 (m, 1H), 4.47-4.40 (m, 1H),4.32-4.26 (m, 1H), 3.81 (s, 2H), 3.54-3.52 (m, 10H), 3.39-3.37 (m, 2H),3.27-3.14 (m, 2H), 2.97-2.86 (m, 1H), 2.73- 2.68 (m, 2H), 2.67-2.63 (m,2H), 2.53- 2.51 (m, 1H), 2.44-2.37 (m, 1H), 2.06-1.96 (m, 1H), 1.85-1.76(m, 2H), 1.11-1.02 (m, 1H), 0.49-0.43 (m, 2H), 0.25-0.20 (m, 2H) 321I-326 OK HG 798.2 11.09 (s, 1H), 10.98 (s, 1H), 9.18 (s, 2H), 9.12 (s,1H), 8.47 (s, 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.99 (s, 1H), 7.64 (d, J =15.6 Hz, 2H), 7.57 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 6.8 Hz, 1H), 7.11(d, J = 8.8 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.57 (s, 1H), 5.05 (dd, J= 5.6, 12.8 Hz, 1H), 4.58 (t, J = 5.2 Hz, 2H), 3.74 (t, J = 5.2 Hz,,2H), 3.63-3.59 (m, 10H), 3.36 (d, J = 6.8 Hz, 2H), 3.22-3.14 (m, 2H),2.94-2.82 (m, 1H), 2.64-2.53 (m, 2H), 2.07-1.99 (m, 1H), 1.21-1.10 (m,1H), 0.61- 0.52 (m, 2H), 0.36-0.30 (m, 2H) 322 I-327 HK GF 922.2 11.09(s, 1H), 9.99 (s, 1H), 8.98 (s, 1H), 8.79 (s, 1H), 8.21 (s, 1H), 8.16(d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.62-7.55 (m, 1H), 7.48(d, J = 8.4 Hz, 2H), 7.44-7.17 (m, 1H), 7.17- 7.08 (m, 3H), 7.07-7.01(m, 2H), 6.60 (t, J = 5.6 Hz, 1H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H),3.79-3.68 (m, 3H), 3.63-3.54 (m, 4H), 3.51-3.41 (m, 4H), 3.21-3.16 (m,2H), 2.94-2.78 (m, 3H), 2.73-2.55 (m, 6H), 2.10- 1.98 (m, 2H), 1.84-1.79(m, 1H), 1.14- 1.02 (m, 1H), 0.51-0.41 (m, 2H), 0.26-0.21 (m, 2H) 323I-328 HO GY 888.4 11.07 (s, 1H), 11.01 (s, 1H), 9.02 (s, 1H), 8.90 (s,1H), 8.32-8.22 (m, 2H), 8.03 (s, 1H), 7.89 (d, J = 8.4 Hz, 2H),7.75-7.66 (m, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.22-7.15 (m,1H), 7.04-6.96 (m, 2H), 6.86 (d, J = 8.4 Hz, 1H), 5.33 (dd, J = 5.2,12.4 Hz, 1H), 4.30-4.21 (m, 2H), 3.79 (s, 2H), 3.55-3.48 (m, 10H), 3.31(s, 3H), 2.93- 2.85 (m, 1H), 2.70-2.64 (m, 4H), 2.04-1.96 (m, 1H),1.85-1.76 (m, 2H 324 I-329 HQ GY 888.5 11.07 (s, 1H), 11.00 (s, 1H),9.01 (s, 1H), 8.89 (s, 1H), 8.29 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.02(s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.73-7.66 (m, 2H), 7.47 (d, J = 8.8Hz, 2H), 7.26 (s, 1H), 7.17 (dd, J = 1.2, 5.2 Hz, 1H), 6.97- 6.90 (m,2H), 6.86-6.82 (m, 1H), 5.35 (dd, J = 5.2, 12.8 Hz, 1H), 4.29-4.19 (m,2H), 3.77 (s, 2H), 3.55-3.50 (m, 11H), 2.95-2.84 (m, 3H), 2.71-2.61 (m,4H), 2.03-1.91 (m, 1H), 1.85- 1.75 (m, 2H) 325 I-330 HR GF 922.1 11.09(s, 1H), 10.00 (s, 1H), 8.97 (s, 1H), 8.79 (s, 1H), 8.23 (s, 1H), 8.16(d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.60-7.53 (m, 1H), 7.48(d, J = 8.4 Hz, 2H), 7.43-7.16 (m, 1H), 7.15- 7.07 (m, 3H), 7.06-7.00(m, 2H), 6.59 (t, J = 5.2 Hz, 1H), 5.05 (dd, J = 5.2, 12.8 Hz, 1H), 3.77(s, 3H), 3.56 (dd, J = 6.0, 11.6 Hz, 4H), 3.51-3.43 (m, 4H), 3.18 (t, J= 6.0 Hz, 2H), 2.94- 2.83 (m, 1H), 2.80 (d, J = 10.8 Hz, 1H), 2.69 (d, J= 11.2 Hz, 1H), 2.60 (d, J = 2.4 Hz, 1H), 2.54-2.58 (m, 1H), 2.55-2.52(m, 2H), 2.48-2.44 (m, 2H), 2.09-1.96 (m, 2H), 1.78-1.82 (m, 1H),1.12-1.02 (m, 1H), 0.50- 0.41 (m, 2H), 0.29-0.16 (m, 2H) 326 I-331 HO GF867.5 10.84 (s, 1H), 9.74 (s, 1H), 8.73 (s, 1H), 8.54 (s, 1H), 7.99 (s,1H), 7.93 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.25 (d, J =8.4 Hz, 2H), 7.20- 6.91 (m, 1H), 6.89-6.83 (m, 2H), 6.82- 6.78 (m, 2H),6.76 (d, J = 8.0 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 5.09 (dd, J = 5.6,12.8 Hz, 1H), 3.55 (s, 2H), 3.31-3.23 (m, 10H), 3.07 (s, 3H), 3.01- 2.89(m, 2H), 2.69-2.62 (m, 1H), 2.46-2.41 (m, 4H), 1.78-1.74(m, 1H),1.61-1.53 (m, 2H), 0.88-0.79 (m, 1H), 0.25-0.19 (m, 2H),-0.01 (q, J =4.8 Hz, 2H) 327 I-332 HQ GF 867.5 11.08 (s, 1H), 9.98 (s, 1H), 8.97 (s,1H), 8.78 (s, 1H), 8.21 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.79 (d, J =8.4 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.43- 7.16 (m, 1H), 7.12 (s, 1H),7.09 (t, J = 5.6 Hz, 1H), 7.06-7.02 (m, 1H), 6.98- 6.91 (m, 2H),6.88-6.82 (m, 1H), 5.36 (dd, J = 5.6, 12.4 Hz, 1H), 3.81 (s, 2H),3.56-3.54 (m, 7H), 3.47-3.45 (m, 4H), 3.19 (t, J = 6.0 Hz, 2H), 2.99-2.85 (m, 3H), 2.77-2.63 (m, 4H), 2.02-1.95 (m, 1H), 1.87-1.77 (m, 2H),1.13-1.01 (m, 1H), 0.50-0.40 (m, 2H), 0.26-0.19 (m, 2H) 328 I-333 HVTert-butyl N- 885.1 11.02 (s, 1H), 9.03 (s, 2H), 8.56 (t, J = [4-[4-[[3-5.6 Hz, 1H), 8.29-8.23 (m, 2H), 8.13 carbamoyl-1- (s, 1H), 8.10 (d, J =8.8 Hz, 2H), 8.02 [4-(5- (d, J = 8.8 Hz, 2H), 7.79 (d, J = 15.2oxopentyl- Hz, 2H), 7.70 (t, J = 6.0 Hz, 1H), 7.60- carbamoyl)- 7.52 (m,1H), 7.27 (s, 1H), 7.18 (dd, phenyl]- J = 1.2 Hz, 1H), 7.09 (d, J = 8.2Hz, pyrazol-4-yl] 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.78 (t, carbamoyl]- J= 5.6 Hz, 1H), 4.51 (dd, J = 6.0, 12.0 oxazol-2-yl]- Hz, 1H), 4.30-4.20(m, 2H), 3.42- 2-pyridyl]-N- 3.16 (m, 6H), 2.83 (t, J = 5.6 Hz, 2H),(2,2,2- 2.69-2.59 (m, 2H), 2.27-2.17 (m, trifluoroethyl)- 1H), 2.03-1.82(m, 3H), 1.61-1.45 carbamate (m, 4H), 1.42-1.34 (m, 2H) (synthesized viaSteps 1-2 of Example 172) 329 I-334 KK GF 950.3 10.87 (s, 1H), 9.76-9.70(m, 1H), 8.79- 8.67 (m, 1H), 8.56 (s, 1H), 7.97- 7.91 (m, 3H), 7.58 (d,J = 8.4 Hz, 2H), 7.36-7.24 (m, 3H), 7.05 (s, 1H), 6.93- 6.84 (m, 3H),6.83-6.76 (m, 2H), 5.99 (d, J = 7.6 Hz, 1H), 4.81 (d, J = 4.8, 12.8 Hz,1H), 3.58 (s, 3H), 3.20- 3.08 (m, 12H), 2.98-2.92 (m, 2H), 2.53 (s, 2H),2.51-2.42 (m, 4H), 2.10 (s, 2H), 1.96 (t, J = 10.0 Hz, 2H), 1.78 (d, J =4.4 Hz, 1H), 1.66 (d, J = 10.0 Hz, 2H), 1.23 (d, J = 11.2 Hz, 2H), 0.84(s, 1H), 0.26-0.19 (m, 2H), 0.02- 0.04 (m, 2H) 330 I-335 HZ GF 950.411.03 (s, 1H), 9.95 (s, 1H), 8.95 (s, 1H), 8.79 (s, 1H), 8.20 (s, 1H),8.16 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 7.6 Hz, 2H), 7.56- 7.48 (m, 3H),7.43-7.14 (m, 1H), 7.11 (s, 1H), 7.07 (t, J = 5.6 Hz, 1H), 7.03 (d, J =5.6 Hz, 1H), 7.00- 6.93 (m, 2H), 6.85 (d, J = 8.4 Hz, 1H), 5.01 (dd, J =5.2, 12.8 Hz, 1H), 3.86-3.83 (m, 2H), 3.60-3.45 (m, 10H), 3.44-3.34 (m,2H), 3.18 (t, J = 6.0 Hz, 2H), 2.92-2.81 (m, 3H), 2.85 (br d, J = 12.5Hz, 1H), 2.75-2.73 (m, 1H), 2.61-2.54 (m, 1H), 2.53-2.52 (m, 1H),2.21-2.14 (m, 2H), 2.01- 1.94 (m, 1H), 1.90-1.84 (m, 2H), 1.46- 1.37 (m,2H), 1.10-1.03 (m, 1H), 0.48-0.43 (m, 2H), 0.25-0.20 (m, 2H) 331 I-336IA GF 936.5 11.09 (s, 1H), 9.99 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H),8.25 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H),7.69-7.64 (m, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.47-7.33 (m, 1H), 7.31 (d,J = 10.4 Hz, 1H), 7.28 (d, J = 5.2 Hz, 1H), 7.15-7.09 (m, 2H), 7.04 (d,J = 5.2 Hz, 1H), 5.12-5.05 (m, 1H), 3.80 (s, 2H), 3.55-3.51 (m, 8H),3.27- 3.22 (m, 4H), 3.20-3.16 (m, 2H), 2.91-2.81 (m, 1H), 2.75-2.65 (m,4H), 2.61-2.57 (m, 4H), 2.57-2.55 (m, 1H), 2.54-2.53 (m, 1H), 2.05- 1.98(m, 1H), 1.60-1.50 (m, 1H), 0.48- 0.43 (m, 2H), 0.25-0.20 (m, 2H) 332I-337 IB GF 936.2 11.06 (s, 1H), 9.95 (s, 1H), 8.96 (s, 1H), 8.78 (s,1H), 8.16 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.65 (d, J =8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.43-7.14 (m, 3H), 7.12 (s, 1H),7.08 (t, J = 5.2 Hz, 1H), 7.06-7.02 (m, 1H), 5.06 (dd, J = 5.2, 12.8 Hz,1H), 3.81 (s, 2H), 3.60-3.53 (m, 4H), 3.53- 3.50 (m, 4H), 3.43-3.35 (m,4H), 3.19 (t, J = 6.0 Hz, 2H), 2.93-2.82 (m, 1H), 2.71 (t, J = 5.6 Hz,2H), 2.63- 2.55 (m, 2H), 2.54 (m, 6H), 2.05-1.97 (m, 1H), 1.13-1.03 (m,1H), 0.49- 0.43 (m, 2H), 0.26-0.20 (m, 2H) 333 I-338 MX GF 922.2 11.10(s, 1H), 9.96 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.21 (s, 1H), 8.17(d, J = 5.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.62-7.49 (m, 3H),7.45-7.15 (m, 1H), 7.12 (s, 1H), 7.10-7.02 (m, 3H), 6.97 (d, J = 8.4 Hz,1H), 6.61 (d, J = 7.2 Hz, 1H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H),4.30-4.19 (m, 1H), 3.87 (s, 2H), 3.72 (t, J = 6.8 Hz, 2H), 3.55 (t, J =5.4 Hz, 2H), 3.54-3.50 (m, 4H), 3.41 (t, J = 5.6 Hz, 2H), 3.20 (t, J =6.4 Hz, 2H), 3.10-2.97 (m, 2H), 2.96- 2.83 (m, 1H), 2.82-2.72 (m, 2H),2.63 (t, J = 4.8 Hz, 2H), 2.60-2.52 (m, 1H), 2.48-2.44 (m, 1H),2.07-1.99 (m, 1H), 1.13-1.02 (m, 1H), 0.50- 0.43 (m, 2H), 0.27-0.20 (m,2H) 334 I-339 IC GF 922.5 11.05 (s, 1H), 9.97 (s, 1H), 8.97 (s, 1H),8.79 (s, 1H), 8.28-8.26 (m, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.85-7.76 (m,2H), 7.59-7.45 (m, 4H), 7.43- 7.15 (m, 1H), 7.14-7.02 (m, 3H), 6.87 (s,1H), 6.78 (d, J = 8.2 Hz, 1H), 5.03 (dd, J = 5.2, 12.8 Hz, 1H), 3.84 (s,3H), 3.70-3.60 (m, 2H), 3.57-3.45 (m, 8H), 3.44-3.38 (m, 2H), 3.19 (t, J= 6.0 Hz, 2H), 3.00-2.83 (m, 3H), 2.62-2.56 (m, 4H), 2.04-1.93 (m, 1H),1.12-1.02 (m, 1H), 0.51-0.42 (m, 2H), 0.28-0.19 (m, 2H) 335 I-340 IE GF948.2 11.08 (s, 1H), 9.97 (s, 1H), 8.97 (s, 1H), 8.78 (s, 1H), 8.31 (s,1H), 8.17 (d, J = 5.2 Hz, 1H), 7.99 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H),7.62-7.53 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 14.0 Hz, 1H),7.15 (d, J = 14.0 Hz,, 2H), 7.10-7.01 (m, 4H), 5.06 (dd, J = 5.2, 12.8Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.49 (t, J = 5.2 Hz, 2H), 3.80 (t, J= 5.2 Hz, 2H), 3.75 (s, 2H), 3.51-3.48 (m, 6H), 3.19 (d, J = 6.0 Hz,2H), 2.94- 2.83 (m, 1H), 2.66-2.55 (m, 4H), 2.06-1.98 (m, 1H), 1.16-1.00(m, 1H), 0.49-0.43 (m, 2H), 0.26-0.19 (m, 2H) 336 I-341 IG GF 948.111.04 (s, 1H), 9.97 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.16 (d, J =5.2 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.61-7.54 (m, 2H),7.50 (d, J = 8.4 Hz, 2H), 7.45-7.15 (m, 1H), 7.12 (s, 1H), 7.10-7.01 (m,3H), 6.95 (dd, J = 2.0, 8.4 Hz, 1H), 5.03 (dd, J = 5.2, 12.8 Hz, 1H),4.50 (t, J = 5.2 Hz, 2H), 4.46 (d, J = 5.6 Hz, 2H), 3.83 (s, 2H), 3.80(t, J = 5.2 Hz, 2H), 3.53-3.44 (m, 6H), 3.19 (t, J = 6.0 Hz, 2H), 2.92-2.80 (m, 1H), 2.72 (t, J = 5.6 Hz, 2H), 2.61-2.53 (m, 2H), 2.03-1.93 (m,1H), 1.13-1.02 (m, 1H), 0.49-0.42 (m, 2H), 0.26-0.20 (m, 2H) 337 I-342IH GF 962.1 11.07 (s, 1H), 9.97 (s, 1H), 8.96 (s, 1H), 8.78 (s, 1H),8.21 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H),7.63-7.53 (m, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.42-7.11 (m, 3H), 7.07 (d,J = 5.2 Hz, 1H), 7.04 (d, J = 6.0 Hz, 2H), 6.74 (t, J = 6.0 Hz, 1H),5.05 (dd, J = 5.2, 12.8 Hz, 1H), 4.52-4.44 (m, 2H), 3.79 (t, J = 4.8 Hz,2H), 3.75- 3.73 (m, 1H), 3.74 (s, 2H), 3.60 (d, J = 6.8 Hz, 2H), 3.47(d, J = 4.8 Hz, 2H), 3.41 (d, J = 6.4 Hz, 4H), 3.19 (t, J = 5.6 Hz, 2H),3.01 (t, J = 6.8 Hz, 2H), 2.93-2.81 (m, 1H), 2.63-2.61 (m, 2H),2.58-2.54 (m, 2H), 2.02-1.99 (m, 1H), 1.10-1.02 (m, 1H), 0.46- 2.44 (m,2H), 0.23-2.22 (m, 2H) 338 I-343 MY GF 962.1 11.04 (s, 1H), 9.96 (s,1H), 8.97 (s, 1H), 8.79 (s, 1H), 8.20 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H),7.80 (d, J = 8.4 Hz, 2H), 7.62-7.56 (m, 2H), 7.47 (d, J = 8.0 Hz, 2H),7.44-7.28 (m, 1H), 7.23 (s, 1H), 7.13 (s, 1H), 7.09-7.01 (m, 3H), 6.91(d, J = 8.3 Hz, 1H), 5.04 (dd, J = 5.2, 12.8 Hz, 1H), 4.46 (t, J = 4.8Hz, 2H), 3.82-3.74 (m, 4H), 3.55- 3.40 (m, 6H), 3.23-3.17 (m, 2H), 3.00(t, J = 6.8 Hz, 2H), 2.93-2.81 (m, 2H), 2.69-2.55 (m, 5H), 2.37-2.32 (m,1H), 2.02-1.96 (m, 1H), 1.08 (s, 1H), 0.49-0.44 (m, 2H), 0.25-0.21 (m,2H) 339 I-344 II GF 949.1 11.11 (s, 1H), 10.00 (s, 1H), 8.98 (s, 1H),8.79 (s, 1H), 8.30-8.20 (m, 2H), 8.17 (d, J = 5.2 Hz, 1H), 7.86-7.76 (m,3H), 7.73 (d, J = 8.4 Hz, 1H), 7.51- 7.44 (m, 3H), 7.44-7.15 (m, 1H),7.14-7.08 (m, 2H), 7.05 (dd, J = 1.2, 5.2 Hz, 1H), 5.41 (s, 2H),5.11-5.03 (m, 1H), 4.56 (t, J = 5.2 Hz, 2H), 3.83 (t, J = 5.2 Hz, 2H),3.77 (s, 2H), 3.56- 3.51 (m, 2H), 3.50-3.43 (m, 4H), 3.19 (t, J = 6.0Hz, 2H), 2.94-2.81 (m, 1H), 2.69-2.63 (m, 2H), 2.58-2.52 (m, 2H),2.06-1.95 (m, 1H), 1.13- 1.02 (m, 1H), 0.50-0.42 (m, 2H), 0.26- 0.20 (m,2H) 340 I-345 NB GF 949.5 10.88 (s, 1H), 9.71 (s, 1H), 8.72 (s, 1H),8.53 (s, 1H), 8.01 (s, 1H), 7.92 (d, J = 5.4 Hz, 1H), 7.60 (d, J = 8.2Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 7.25-7.16 (m, 2H), 7.05(s, 1H), 6.91-6.87 (m, 1H), 6.86-6.78 (m, 2H), 5.12 (s, 2H), 4.88 (dd, J= 5.2, 12.8 Hz, 1H), 4.32 (t, J = 5.2 Hz, 2H), 3.63-3.56 (m, 2H), 3.50(s, 2H), 3.30 (s, 2H), 3.24 (d, J = 5.4 Hz, 4H), 2.96 (d, J = 6.0 Hz,2H), 2.71-2.61 (m, 1H), 2.47-2.41 (m, 4H), 1.86-1.71 (m, 2H), 0.83 (d, J= 5.6 Hz, 1H), 0.27- 0.19 (m, 2H), 0.01 (d, J = 4.4 Hz, 2H) 341 I-346 IJGF 963.1 11.08 (s, 1H), 9.96 (s, 1H), 8.97 (s, 1H), 8.78 (s, 1H), 8.16(d, J = 5.2 Hz, 1H), 7.83-7.76 (m, 3H), 7.75 (s, 1H), 7.53-7.44 (m, 4H),7.43-7.15 (m, 1H), 7.12 (s, 1H), 7.08 (t, J = 5.6 Hz, 1H), 7.06-7.02 (m,1H), 5.10 (dd, J = 5.2, 12.8 Hz, 1H), 4.58 (t, J = 5.2 Hz, 2H), 4.41 (t,J = 6.0 Hz, 2H), 3.81 (t, J = 5.2 Hz, 2H), 3.77 (s, 2H), 3.52-3.49 (m,2H), 3.46-3.42 (m, 4H), 3.25 (t, J = 6.0 Hz, 2H), 3.19 (t, J = 6.0 Hz,2H), 2.94-2.84 (m, 1H), 2.65 (t, J = 5.6 Hz, 2H), 2.59-2.54 (m, 2H),2.09-1.98 (m, 1H), 1.13-1.01 (m, 1H), 0.49- 0.43 (m, 2H), 0.26-0.21 342I-347 ND GF 963.1 11.09 (s, 1H), 9.95 (s, 1H), 8.97 (s, 1H), 8.78 (s,1H), 8.22 (d, J = 6.8 Hz, 2H), 8.17 (d, J = 5.2 Hz, 1H), 7.81- 7.76 (m,3H), 7.63 (s, 1H), 7.50-7.44 (m, 3H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H),7.29 (s, 1H), 7.12 (s, 1H), 7.10-7.03 (m, 2H), 5.12 (dd, J = 5.6, 12.8Hz, 1H), 4.54 (t, J = 5.2 Hz, 2H), 4.43 t, J = 6.4 Hz, 2H), 3.82 (t, J =5.2 Hz, 3H), 3.75 (s, 3H), 3.52-3.48 (m, 5H), 3.45 (s, 2H), 2.95-2.84(m, 1H), 2.69- 2.60 (m, 5H), 2.34-2.33 (m, 1H), 2.08- 2.00 (m, 1H),1.12-1.03 (m, 1H), 0.48-0.44 (m, 2H), 0.26-0.21 (m, 2H) 343 I-348 IN GF979.5 11.07 (s, 1H), 9.95 (s, 1H), 8.96 (s, 1H), 8.79 (s, 1H), 8.24-8.21(m, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.56 (t, J= 8.4 Hz, 1H), 7.53-7.45 (m, 2H), 7.43-7.15 (m, 1H), 7.14-7.10 (m, 2H),7.07 (t, J = 5.6 Hz, 1H), 7.05-7.00 (m, 2H), 6.57 (t, J = 5.6 Hz, 1H),5.05 (dd, J = 5.2, 12.8 Hz, 1H), 3.57-3.47 (m, 16H), 3.19 (t, J = 6.0Hz, 2H), 2.94-2.83 (m, 1H), 2.75-2.68 (m, 2H), 2.62-2.55 (m, 2H),2.44-2.41 (m, 4H), 2.37- 2.34 (m, 4H), 2.05-1.99 (m, 1H), 1.12- 1.03 (m,1H), 0.49-0.42 (m, 2H), 0.26-0.19 (m, 2H) 344 I-349 NE GF 979.2 11.04(s, 1H), 9.97 (s, 1H), 8.96 (s, 1H), 8.79 (s, 1H), 8.22 (s, 2H), 8.16(d, J = 5.2 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 1H),7.50 (d, J = 8.4 Hz, 2H), 7.45-7.15 (m, 1H), 7.14-7.03 (m, 4H), 7.00 (s,1H), 6.88 (d, J = 8.4 Hz, 1H), 5.03 (dd, J = 5.2, 12.8 Hz, 1H), 3.81 (s,2H), 3.59-3.50 (m, 10H), 3.19 (t, J = 6.4 Hz, 2H), 2.93- 2.84 (m, 1H),2.71-2.68 (m, 2H), 2.60-2.56 (m, 2H), 2.44 (t, J = 5.6 Hz, 4H),2.41-2.29 (m, 8H), 2.04-1.93 (m, 1H), 1.05-0.94 (m, 1H), 0.51- 0.40 (m,2H), 0.25-0.22 (m, 2H) 345^(b) I-350 IO GF 991.6 11.13 (s, 2H), 10.32(s, 1H), 10.11 (s, 1H), 9.11 (s, 1H), 9.04 (s, 1H), 8.90 (s, 1H), 8.16(d, J = 6.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H),7.64-7.58 (m, 1H), 7.34-7.25 (m, 1H), 7.20-7.05 (m, 3H), 6.64- 6.55 (m,1H), 5.08 (dd, J = 5.4, 13.0 Hz, 1H), 4.48-4.14 (m, 10H), 3.71 (d, J =5.2 Hz, 4H), 3.64 (d, J = 4.8 Hz, 9H), 3.37 (s, 2H), 3.23 (d, J = 6.8Hz, 2H), 3.16 (s, 2H), 2.97-2.85 (m, 1H), 2.64 (s, 1H), 2.59 (s, 1H),2.11-1.99 (m, 1H), 1.11 (s, 1H), 0.51 (d, J = 8.4 Hz, 2H), 0.27 (d, J =4.4 Hz, 2H) 346 I-351 NG GF 991.3 11.07 (s, 1H), 10.33 (s, 2H), 10.12(s, 1H), 9.17 (s, 1H), 9.05 (s, 1H), 8.89 (s, 1H), 8.15 (d, J = 6.0 Hz,1H), 7.98 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.59 (d, J =8.4 Hz, 1H), 7.47- 7.07 (m, 4H), 7.02 (d, J = 1.6 Hz, 1H), 6.91 (dd, J =1.6, 8.4 Hz, 1H), 5.04 (dd, J = 5.2, 12.8 Hz, 1H), 4.46-4.19 (m, 10H),3.70 (d, J = 5.2 Hz, 10H), 3.37 (s, 4H), 3.23 (d, J = 6.8 Hz, 2H), 3.16(d, J = 5.6 Hz, 2H), 2.93-2.83 (m, 1H), 2.64-2.52 (m, 2H), 2.04- 1.94(m, 1H), 1.15-1.05 (m, 1H), 0.60- 0.47 (m, 2H), 0.33-0.26 (m, 2H)347^(c) I-352 OK IW 801.1 11.09 (s, 1H), 9.97 (s, 1H), 9.40-9.38 (m,2H), 8.82 (s, 1H), 8.80 (s, 1H), 8.43 (s, 1H), 8.00 (s, 1H), 7.90 (d, J= 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.59-7.52 (m, 1H), 7.31 (t, J =56.0 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H),5.08-5.02 (m, 1H), 4.12-4.30 (m, 2H), 3.95 (s, 3H), 3.75 (t, J = 5.2 Hz,2H), 3.59-3.68 (m, 6H), 3.47 ( t, J = 5.2 Hz, 2H), 3.20- 3.00 (s, 2H),2.96-2.78 (m, 1H), 2.64- 2.56 (m, 2H), 2.08-1.97 (m, 1H) 348^(c) I-353IX IW 801.4 11.04 (s, 1H), 9.88 (s, 1H), 8.78-8.74 (m, 2H), 8.43 (s,1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.57-7.53 (m,1H), 7.47 (d, J = 8.8 Hz, 2H), 7.43-7.12 (m, 2H), 7.00 (d, J = 2.0 Hz,1H), 6.89 (dd, J = 2.0, 8.4 Hz, 1H), 5.02 (dd, J = 5.2, 12.8 Hz, 1H),3.94 (s, 3H), 3.77 (s, 2H), 3.62- 3.54 (m, 8H), 3.35 (d, J = 5.6 Hz,2H), 2.92-2.81 (m, 1H), 2.67 (t, J = 5.6 Hz, 2H), 2.60-2.52 (m, 2H),2.03-1.93 (m, 1H) 349 I-354 IX GF 867.5 11.05 (s, 1H), 9.98 (s, 1H),8.96 (s, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 8.15 (d, J = 5.3 Hz, 1H), 7.78(d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H),7.42-7.17 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H), 7.11 (s, 1H), 7.08 (t, J =5.5 Hz, 1H), 7.03 (dd, J = 1.2, 5.2 Hz, 1H), 7.00 (d, J = 1.6 Hz, 1H),6.88 (dd, J = 2.0, 8.4 Hz, 1H), 5.02 (dd, J = 5.6, 12.8 Hz, 1H), 3.76(s, 2H), 3.62-3.55 (m, 8H), 3.22-3.15 (m, 4H), 2.95-2.81 (m, 1H), 2.67-2.64 (m, 2H), 2.57-2.53 (m, 2H), 2.02- 1.92 (m, 1H), 1.11-1.02 (m, 1H),0.47-0.43 (m, 2H), 0.24-0.20 (m, 2H 350 I-355 IZ GF 792.1 11.12 (s, 1H),9.99 (s, 1H), 8.97 (s, 1H), 8.78 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H),7.83-7.77 (d, J = 8.4 Hz, 2H), 7.76-7.72 (m, 2H), 7.72-7.67 (m, 1H),7.45 (d, J = 8.4 Hz, 2H), 7.29 (t, J = 14.0 Hz, 1H), 7.14-7.07 (m, 2H),7.04 (dd, J = 1.2, 5.6 Hz, 1H), 5.13 (dd, J = 5.2, 12.4 Hz, 1H), 3.52(s, 2H), 3.18 (t, J = 6.0 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 2.94-2.83(m, 1H), 2.64-2.53 (m, 2H), 2.41 (t, J = 6.8 Hz, 2H), 2.15 (s, 3H),2.09-2.02 (m, 1H), 1.87-1.75 (m, 2H), 1.13-1.02 (m, 1H), 0.49-0.40 (m,2H), 0.26-0.19 (m, 2H) 351^(c) I-356 IZ JA 716.0 11.13 (d, J = 7.6 Hz,2H), 11.05 (s, 1H), 9.17 (s, 1H), 9.01 (s, 1H), 8.94 (d, J = 6.0 Hz,2H), 8.15-8.01 (m, 5H), 7.89-7.72 (m, 6H), 5.15 (dd, J = 3.6, 12.4 Hz,1H), 4.48-4.26 (m, 2H), 3.12 (d, J = 6.8 Hz, 3H), 2.69 (d, J = 4.8 Hz,3H), 2.62-2.54 (m, 3H), 2.22- 1.98 (m, 4H) 352 I-357 FU GF 778.1 11.11(s, 1H), 9.98 (s, 1H), 8.97 (s, 1H), 8.78 (s, 1H), 8.29 (s, 2H), 8.16(d, J = 4.8 Hz, 1H), 7.65-7.89 (m, 5H), 7.56-7.46 (m, 2H), 7.45-7.15 (m,1H), 7.14-7.00 (m, 3H), 5.30-4.98 (m, 1H), 3.76 (s, 2H), 3.19 (t, J =5.6 Hz, 2H), 3.05-3.13 (m, 2H), 2.83-2.95 (m, 1H), 2.65-2.56 (m, 4H),2.00- 2.12 (m, 1H), 1.72-1.86 (m, 2H), 0.98- 1.15 (m, 1H), 0.38-0.51 (m,2H), 0.15- 0.27 (m, 2H) 353^(c) I-358 FU JA 702.4 11.15-11.03 (m, 2H),9.09 (s, 1H), 8.91 (s, 1H), 8.87-8.83 (m, 2H), 8.33 (s, 1H), 8.03 (s,1H), 7.99-7.94 (m, 2H), 7.93-7.87 (m, 2H), 7.79-7.73 (m, 3H), 7.72-7.69(m, 1H), 7.52- 7.46 (m, 2H), 5.16-5.10 (m, 1H), 3.76 (s, 2H), 3.14-3.04(m, 2H), 2.93- 2.87 (m, 1H), 2.64-2.61 (m, 1H), 2.60- 2.57 (m, 1H),2.57-2.55 (m, 2H), 2.09-2.03 (m, 1H), 1.85-1.76 (m, 2H 354^(c) I-359 NHJD 681.1 11.13 (s, 1H), 10.35-10.17 (m, 1H), 10.16-9.81 (m, 2H),9.27-9.05 (m, 1H), 8.94-8.84 (m, 3H), 8.23-8.07 (m, 3H), 8.00-7.90 (m,4H), 7.84- 7.66 (m, 2H), 7.49-7.15 (m, 1H), 5.23- 5.08 (m, 1H),4.72-4.56 (m, 2H), 4.33 (s, 2H), 3.10-2.80 (m, 1H), 2.68- 2.52 (m, 2H),2.09-1.97 (m, 1H) 355 I-360 IZ JC 920.2 11.10 (s, 1H), 9.98 (s, 1H),8.99 (s, 1H), 8.79 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 8.4Hz, 2H), 7.77- 7.71 (m, 2H), 7.70-7.66 (m, 1H), 7.61 (t, J = 6.4 Hz,1H), 7.45 (d, J = 8.4 Hz, 2H), 7.43-7.14 (m, 3H), 5.13 (dd, J = 5.2,12.8 Hz, 1H), 4.30-4.18 (m, 2H), 3.52 (s, 2H), 3.07 (t, J = 7.2 Hz, 2H),2.96-2.82 (m, 1H), 2.65-2.51 (m, 2H), 2.42 (t, t, J = 7.2 Hz, 2H), 2.16(s, 3H), 2.09-2.01 (m, 1H), 1.86-1.79 (m, 2H) 356 I-361 FU JC 806.311.11 (s, 1H), 9.99 (s, 1H), 9.00 (s, 1H), 8.79 (s, 1H), 8.28-8.24 (m,2H), 7.82-7.75 (m, 4H), 7.73-7.69 (m, 1H), 7.61 (t, J = 6.4 Hz, 1H),7.50 (d, J = 8.4 Hz, 2H), 7.27 (s, 1H), 7.22 (d, J = 5.2 Hz, 1H), 7.16(s, 1H), 5.14 (dd, J = 5.2, 12.8 Hz, 1H), 4.25 (dd, J = 6.8, 9.6 Hz,2H), 3.77 (s, 2H), 3.10 (t, J = 7.6 Hz, 2H), 2.96-2.83 (m, 1H), 2.68-2.63 (m, 1H), 2.60-2.57 (m, 3H), 2.34 (s, 1H), 2.11-2.02 (m, 1H), 1.86-1.77 (m, 2H) 357 I-362 GL GF 836.1 11.13 (s, 1H), 10.00 (s, 1H), 8.97(s, 1H), 8.78 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.85-7.73 (m, 4H),7.72-7.66 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.43- 7.15 (m, 1H),7.14-7.07 (m, 2H), 7.05 (dd, J = 1.2, 5.2 Hz, 1H), 5.13 (dd, J = 5.2,12.8 Hz, 1H), 3.57 (s, 2H), 3.54-3.50 (m, 4H), 3.19 (t, J = 6.0 Hz, 2H),3.08 (t, J = 7.6 Hz, 2H), 2.93-2.84 (m, 1H), 2.64-2.58 (m, 1H),2.58-2.56 (m, 1H), 2.55-2.53 (m, 2H), 2.19 (s, 3H), 2.09-2.01 (m, 1H),1.91-1.81 (m, 2H), 1.13-1.03 (m, 1H), 0.50-0.42 (m, 2H), 0.27- 0.19 (m,2H) 358 I-363 GL JD 767.4 11.10 (s, 1H), 10.09 (s, 1H), 9.05 (s, 1H),8.90-8.81 (m, 2H), 8.78 (s, 1H), 8.03-7.93 (m, 2H), 7.83-7.78 (m, 2H),7.77-7.72 (m, 2H), 7.71-7.66 (m, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.43-7.13 (m, 1H), 5.12 (dd, J = 5.2, 12.8 Hz, 1H), 3.56 (s, 2H), 3.51 (t, J= 6.0 Hz, 2H), 3.42 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 7.6 Hz, 2H),2.94-2.83 (m, 1H), 2.63-2.57 (m, 1H), 2.56-2.53 (m, 2H), 2.53-2.52 (m,1H), 2.19 (s, 3H), 2.08-2.01 (m, 1H), 1.90-1.80 (m, 2H) 359^(c) I-364 FUJM 780.1 11.11 (s, 1H), 10.29-10.23 (m, 1H), 9.20-9.16 (m, 1H), 9.09 (s,1H), 9.01- 8.92 (m, 3H), 8.89 (s, 1H), 8.24- 8.14 (m, 2H), 8.01-7.90 (m,2H), 7.84- 7.77 (m, 2H), 7.74-7.66 (m, 1H), 7.62-7.54 (m, 1H), 7.42-7.29(m, 1H), 5.30-5.08 (m, 1H), 3.77 (s, 2H), 3.36-3.09 (m, 3H), 3.04-2.97(m, 3H), 2.92-2.83 (m, 1H), 2.64-2.56 (m, 2H), 2.14-1.96 (m, 2H) 360^(c)I-365 IZ JD 723.3 11.10 (s, 1H), 10.09 (s, 1H), 9.05 (s, 1H), 8.84 (d, J= 6.0 Hz 2H), 8.78 (s, 1H), 7.99 (d, J = 6.0 Hz 2H), 7.79 (d, J = 8.4Hz, 2H), 7.77-7.71 (m, 2H), 7.71-7.66 (m, 1H), 7.45 (d, J = 8.8 Hz, 2H),7.29 (d, J = 54 Hz, 1H), 5.13 (dd, J = 5.2, 12.8 Hz, 1H), 3.52 (s, 2H),3.14-3.02 (m, 2H), 2.93-2.84 (m, 1H), 2.65-2.52 (m, 2H), 2.41 (t, J =7.2 Hz, 2H), 2.15 (s, 3H), 2.10-2.02 (m, 1H), 1.86-1.79 (m, 2H) 361^(c)I-366 FU JD 709.1 11.12 (s, 1H), 10.23 (s, 1H), 9.41 (s, 2H), 8.90 (d, J= 6.0 Hz, 2H), 8.86 (s, 1H), 8.11 (d, J = 6.4 Hz, 2H), 7.94 (d, J = 8.8Hz, 2H), 7.87-7.67 (m, 5H), 7.32 (t, J = 14.0 Hz,, 1H), 5.14 (dd, J =5.2, 12.8 Hz, 1H), 4.19 (t, J = 5.2 Hz, 2H), 3.12 (t, J = 7.2 Hz, 2H),3.04- 2.81 (m, 3H), 2.66-2.53 (m, 2H), 2.14- 1.97 (m, 3H) 362 I-367 GWGF 822.4 10.89 (s, 1H), 9.77 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.00(s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.54-7.50(m, 2H), 7.49-7.45 (m, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.20- 6.91 (m,1H), 6.91-6.85 (m, 2H), 6.78-6.82 (m, 1H), 4.90 (dd, J = 5.2, 12.8 Hz,1H), 3.56 (s, 2H), 3.23 (t, J = 5.6 Hz, 2H), 3.19 (t, J = 6.0 Hz, 2H),2.95 (t, J = 6.0 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.71-2.59 (m, 1H),2.46- 2.42 (m, 2H), 2.40-2.33(m, 1H), 2.32- 2.29 (m, 1H), 1.86-1.78 (m,1H), 1.66-1.59 (m, 2H), 0.88-0.79 (m, 1H), 0.25-0.20 (m, 2H), 0.02-−0.03(m, 2H) 363^(c) I-368 GW JD 753.3 11.12 (s, 1H), 10.12 (s, 1H), 9.06 (s,1H), 8.84 (d, J = 6.0 Hz, 2H), 8.79 (s, 1H), 8.01-7.95 (m, 2H),7.85-7.80 (m, 2H), 7.79-7.72 (m, 2H), 7.71- 7.68 (m, 1H), 7.54-7.47 (m,2H), 7.43- 7.14 (m, 1H), 5.13 (dd, J = 5.6, 12.8 Hz, 1H), 3.83 (s, 2H),3.48 (t, J = 5.6 Hz, 2H), 3.42 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 7.6 Hz,2H), 2.94-2.83 (m, 1H), 2.71 (t, J = 5.6 Hz, 2H), 2.64- 2.51 (m, 2H),2.09-2.01 (m, 1H), 1.90- 1.82 (m, 2H) 364 I-369 JH GF 792.1 11.12 (s,1H), 10.01 (s, 1H), 8.98 (s, 1H), 8.79 (s, 1H), 8.16 (d, J = 5.2 Hz,1H), 7.84-7.77 (m, 4H), 7.77-7.71 (m, 1H), 7.49-7.44 (m, 2H), 7.44- 7.16(m, 1H), 7.12 (s, 1H), 7.11-7.08 (m, 1H), 7.04 (dd, J = 1.2, 5.2 Hz,1H), 5.14 (dd, J = 5.6, 13.0 Hz, 1H), 3.51 (s, 2H), 3.19 (t, J = 6.0 Hz,2H), 2.95- 2.86 (m, 1H), 2.85-2.80 (m, 2H), 2.64- 2.55 (m, 2H), 2.39 (d,J = 6.8 Hz, 2H), 2.14 (s, 3H), 2.09-2.00 (m, 1H), 1.90-1.80 (m, 2H),1.12-1.03 (m, 1H), 0.49-0.43 (m, 2H), 0.26-0.21 (m, 2H) 365^(c) I-370 JHGE 716.4 11.11 (s, 2H), 9.10-9.07 (m, 1H), 8.93- 8.91 (m, 1H), 8.85 (d,J = 6.0 Hz, 2H), 8.04 (s, 1H), 7.96 (d, J = 6.0 Hz, 2H), 7.90 (d, J =8.4 Hz, 2H), 7.83- 7.76 (m, 3H), 7.71 (d, J = 7.6 Hz, 1H), 7.45 (d, J =8.4 Hz, 2H), 5.14 (dd, J = 5.6, 13.2 Hz, 1H), 3.51 (s, 2H), 2.94- 2.86(m, 1H), 2.83 (d, J = 7.2 Hz, 2H), 2.64-2.54 (m, 2H), 2.39-2.35 (m, 2H),2.15 (s, 3H), 2.08-2.00 (m, 1H), 1.89-1.81 (m, 2H) 366 I-371 JI GF 778.411.14 (s, 1H), 10.03 (s, 1H), 8.98 (s, 1H), 8.79 (s, 1H), 8.30 (s, 1H),8.16 (d, J = 5.2 Hz, 1H), 7.87-7.77 (m, 4H), 7.72 (d, J = 7.2 Hz, 1H),7.51 (d, J = 8.4 Hz, 2H), 7.46-7.15 (m, 1H), 7.15- 7.08 (m, 2H), 7.05(d, J = 5.2 Hz, 1H), 5.15 (dd, J = 5.2, 12.8 Hz, 1H), 3.78 (s, 2H), 3.19(t, J = 6.0 Hz, 2H), 2.95-2.81 (m, 3H), 2.71-2.55 (m, 4H), 2.09-2.01 (m,1H), 1.89-1.75 (m, 2H), 1.07-1.06 (m, 1H), 0.51- 0.41 (m, 2H), 0.23-0.22(m, 2H) 367^(c) I-372 JI GE 702.3 11.10 (s, 2H), 9.08 (s, 1H), 8.92 (s,1H), 8.85 (d, J = 5.6 Hz, 2H), 8.29 (s, 1H), 8.06 (s, 1H), 7.99-7.89 (m,4H), 7.83 (d, J = 7.6 Hz, 1H), 7.81-7.75 (m, 2H), 7.72 (d, J = 7.6 Hz,1H), 7.52 (d, J = 8.2 Hz, 2H), 5.14 (dd, J = 5.2, 12.8 Hz, 1H),3.86-3.75 (m, 2H), 2.95- 2.83 (m, 3H), 2.65-2.54 (m, 4H), 2.10-2.01 (m,1H), 1.89-1.81 (m, 1H) 368^(c) I-373 JJ JD 681.3 11.11 (s, 1H), 10.09(s, 1H), 9.06 (s, 1H), 8.85 (d, J = 6.0 Hz, 2H), 8.79 (s, 1H), 8.39 (s,1H), 7.99 (d, J = 6.0 Hz, 2H), 7.95 (s, 1H), 7.90-7.86 (m, 2H), 7.82 (d,J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.43-7.15 (m, 1H), 5.20- 5.08(m, 1H), 3.91 (s, 2H), 3.76 (s, 2H), 2.94-2.87 (m, 1H), 2.65-2.61 (m,1H), 2.60-2.57 (m, 1H), 2.09- 2.00 (m, 1H) 369 I-374 JH JC 820.4 11.09(s, 1H), 9.98 (s, 1H), 8.99 (s, 1H), 8.79 (s, 1H), 8.25 (d, J = 5.2 Hz,1H), 7.83-7.78 (m, 4H), 7.75-7.71 (m, 1H), 7.60 (t, J = 6.4 Hz, 1H),7.47- 7.43 (m, 2H), 7.30-7.16 (m, 3H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H),4.30- 4.20 (m, 2H), 3.51 (s, 2H), 2.95-2.85 (m, 1H), 2.83 (t, J = 7.2Hz, 2H), 2.64- 2.56 (m, 2H), 2.38 (t, J = 6.8 Hz, 2H), 2.14 (s, 3H),2.09-2.01 (m, 1H), 1.89-1.82 (m, 2H) 370 I-375 JI JC 806.3 11.11 (s,1H), 10.01 (s, 1H), 9.00 (s, 1H), 8.82 (s, 1H), 8.26 (d, J = 5.2 Hz,1H), 8.19 (s, 1H), 7.89-7.80 (m, 4H), 7.75-7.72 (m, 1H), 7.62 (t, J =6.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.44- 7.17 (m, 1H), 7.27 (s, 1H),7.22 (dd, J = 1.2, 5.2 Hz, 1H), 5.15 (dd, J = 5.2, 12.8 Hz, 1H),4.32-4.20 (m, 2H), 3.90 (s, 2H), 2.95-2.82 (m, 3H), 2.70- 2.53 (m, 4H),2.11-2.01 (m, 1H), 1.94- 1.83 (m, 2H) 371 I-376 JK GF 836.4 11.12 (s,1H), 9.99 (s, 1H), 8.97 (s, 1H), 8.78 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H),7.84-7.81 (m, 2H), 7.78 (d, J = 6.0 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H),7.46 (d, J = 8.4 Hz, 2H), 7.42-7.14 (m, 1H), 7.12-7.08 (m, 2H), 7.06-7.01 (m, 1H), 5.18-5.08 (m, 1H), 3.56 (s, 2H), 3.53-3.48 (m, 4H), 3.21-3.14 (m, 2H), 2.92-2.86 (m, 1H), 2.84- 2.80 (m, 2H), 2.63-2.59 (m, 1H),2.58-2.57 (m, 1H), 2.56-2.54 (m, 2H), 2.19 (s, 3H), 2.07-2.02 (m, 1H),1.89-1.84 (m, 2H), 1.11-1.04 (m, 1H), 0.47-0.42 (m, 2H), 0.24-0.20 (m,2H) 372^(c) I-377 JK JD 767.4 11.11 (s, 1H), 10.09 (s, 1H), 9.06 (s,1H), 8.87-8.82 (m, 2H), 8.79 (s, 1H), 8.01-7.97 (m, 2H), 7.86-7.77 (m,4H), 7.72 (d, J = 7.2 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.44-7.12 (m,1H), 5.18-5.11 (m, 1H), 3.58 (s, 2H), 3.54- 3.51 (m, 2H), 3.41-3.40 (m,2H), 2.95-2.88 (m, 1H), 2.87-2.82 (m, 2H), 2.64-2.58 (m, 1H), 2.57-2.54(m, 2H), 2.54-2.52 (m, 1H), 2.21 (s, 3H), 2.08-2.01 (m, 1H), 1.92-1.84(m, 2H) 373^(c) I-378 JI JM 780.3 11.09 (s, 1H), 10.20 (s, 1H), 9.08 (s,1H), 8.93-8.80 (m, 3H), 8.30 (s, 1H), 8.03-7.97 (m, 2H), 7.95-7.93 (m,2H), 7.84-7.72 (m, 2H), 7.65-7.54 (m, 3H), 7.47-7.16 (m, 1H), 5.15 (dd,J = 5.2, 12.8 Hz, 1H), 3.73-3.46 (m, 2H), 3.45-3.20 (m, 2H), 3.03-2.85(m, 4H), 2.84-2.52 (m, 6H), 2.10- 1.96 (m, 1H), 1.90-1.68 (m, 2H)374^(c) I-379 JH JD 723.3 11.10 (s, 1H), 10.11 (s, 1H), 9.03 (s, 1H),8.83 (d, J = 5.6 Hz, 2H), 8.76 (s, 1H), 7.99 (d, J = 5.6 Hz, 2H), 7.84-7.76 (m, 4H), 7.75-7.67 (m, 1H), 7.49- 7.42 (m, 2H), 7.42-7.14 (m, 1H),5.13 (dd, J = 5.5, 13.0 Hz, 1H), 3.50 (s, 2H), 2.96-2.85 (m, 1H), 2.83(d, J = 7.2 Hz, 2H), 2.63-2.53 (m, 2H), 2.37 (t, J = 6.8 Hz, 2H), 2.14(s, 3H), 2.08- 2.00 (m, 1H), 1.89-1.81 (m, 2H) 375^(c) I-380 JI JD 709.311.11 (s, 1H), 10.10 (s, 1H), 9.06 (s, 1H), 8.89-8.82 (m, 2H), 8.79 (s,1H), 8.25 (s, 1H), 8.02-7.97 (m, 2H), 7.87- 7.77 (m, 4H), 7.73-7.71 (m,1H), 7.51 (d, J = 8.4 Hz, 2H), 7.44-7.14 (m, 1H), 5.14 (dd, J = 5.2,12.8 Hz, 1H), 3.79 (s, 2H), 2.96-2.78 (m, 3H), 2.69-2.52 (m, 4H),2.12-2.02 (m, 1H), 1.88-1.77 (m, 2H) 376 I-381 JR GF 822.1 11.13 (s,1H), 10.01 (s, 1H), 8.98 (s, 1H), 8.80 (s, 1H), 8.21-8.10 (m, 2H),7.87-7.78 (m, 4H), 7.73 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 2H),7.46- 7.15 (m, 1H), 7.14-7.08 (m, 2H), 7.08-7.01 (m, 1H), 5.20-5.10 (m,1H), 3.91-3.79 (m, 2H), 3.52-3.45 (m, 2H), 3.44-3.35 (m, 2H), 3.24- 3.22(m, 2H), 2.97-2.81 (m, 3H), 2.77- 2.58 (m, 4H), 2.12-2.01 (m, 1H),1.94-1.82 (m, 2H), 1.14-1.02 (m, 1H), 0.53-0.41 (m, 2H), 0.29-0.19 (m,2H) 377^(c) I-382 JR JD 753.3 11.11 (s, 1H), 10.28 (s, 1H), 9.48 (s,2H), 9.18 (s, 1H), 8.95 (d, J = 6.4 Hz, 2H), 8.87 (s, 1H), 8.20 (d, J =6.0 Hz, 2H), 8.04-7.90 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.81-7.73 (m,3H), 7.49- 7.19 (m, 1H), 5.16-5.11 (m, 1H), 4.23 (t, J = 5.2 Hz, 2H),3.70 (t, J = 5.2 Hz, 2H), 3.45 (t, J = 6.4 Hz, 2H), 3.10 (s, 2H),2.95-2.78 (m, 3H), 2.65- 2.51 (m, 2H), 2.10-2.00 (m, 1H), 1.95- 1.86 (m,2H) 378 I-383 II GF 949.2 9.96 (s, 1H), 8.96 (s, 1H), 8.78 (s, 1H), 8.16(d, J = 5.2 Hz, 1H), 7.87-7.81 (m, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.65(d, J = 8.4 Hz, 1H), 7.52-7.44 (m, 3H), 7.43-7.15 (m, 1H), 7.12 (s, 1H),7.07 (t, J = 5.6 Hz, 1H), 7.05-7.02 (m, 1H), 5.58 (s, 2H), 5.09 (dd, J =5.6, 12.8 Hz, 1H), 4.66 (t, J = 5.2 Hz, 2H), 3.84 (t, J = 5.2 Hz, 2H),3.75 (s, 2H), 3.51-3.47 (m, 2H), 3.45-3.40 (m, 4H), 3.19 (t, J = 6.0 Hz,2H), 2.93- 2.81 (m, 1H), 2.63 (t, J = 5.6 Hz, 2H), 2.60-2.54 (m, 2H),2.06-1.97 (m, 1H), 1.15-1.00 (m, 1H), 0.49-0.42 (m, 2H), 0.26-0.19 (m,2H) 379 I-384 NT GF 936.4 11.01 (s, 1H), 9.99 (s, 1H), 8.96 (s, 1H),8.82 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.56(d, J = 8.8 Hz, 2H), 7.46-7.16 (m, 2H), 7.12 (s, 1H), 7.10-7.02 (m, 2H),6.93 (d, J = 7.2 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.31 (s, 1H), 5.12(dd, J = 5.2, 13.2 Hz, 1H), 4.35-4.08 (m, 2H), 3.94 (s, 2H), 3.67-3.46(m, 8H), 3.36- 3.30 (m, 1H), 3.19 (t, J = 6.0 Hz, 2H), 2.96-2.94 (m,2H), 2.83 (t, J = 5.2 Hz, 2H), 2.62-2.55 (m, 2H), 2.69- 2.54 (m, 1H),2.36-2.19 (m, 3H), 2.11-2.00 (m, 1H), 1.93-1.91 (m, 2H), 1.57-1.39 (m,2H), 1.14-0.96 (m, 1H), 0.54-0.40 (m, 2H), 0.28- 0.12 (m, 2H) 380 I-385NU GF 906.2 11.08 (s, 1H), 9.97 (s, 1H), 8.96 (s, 1H), 8.79 (s, 1H),8.16 (d, J = 5.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.60- 7.50 (m, 3H),7.43-7.12 (m, 2H), 7.11 (s, 1H), 7.07 (t, J = 5.2 Hz, 1H), 7.05- 7.00(m, 2H), 6.23 (d, J = 8.0 Hz, 1H), 5.04 (dd, J = 5.2, 12.8 Hz, 1H), 3.88(s, 2H), 3.66-3.56 (m, 1H), 3.55-3.49 (m, 4H), 3.19 (t, J = 6.0 Hz, 2H),2.93- 2.85 (m, 1H), 2.85-2.79 (m, 2H), 2.79-2.73 (m, 2H), 2.63-2.55 (m,2H), 2.55-2.53 (m, 2H), 2.25 (t, J = 10.4 Hz, 2H), 2.08-1.97 (m, 1H),1.96- 1.84 (m, 2H), 1.56-1.41 (m, 2H), 1.13-1.01 (m, 1H), 0.50-0.41 (m,2H), 0.25-0.18 (m, 2H) 381 I-386 JY GF 994.2 11.08 (s, 1H), 9.97 (s,1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.88-7.80 (m,2H), 7.60-7.49 (m, 3H), 7.44-7.15 (m, 1H), 7.15- 7.10 (m, 2H), 7.07 (t,J = 5.2 Hz, 1H), 7.05-7.01 (m, 2H), 6.22 (d, J = 8.0 Hz, 1H), 5.05 (dd,J = 5.2, 12.8 Hz, 1H), 3.88 (s, 2H), 3.62-3.55 (m, 1H), 3.55-3.47 (m,12H), 3.19 (t, J = 6.0 Hz, 2H), 2.94-2.84 (m, 1H), 2.83- 2.74 (m, 4H),2.63-2.52 (m, 2H), 2.48- 2.42 (m, 2H), 2.26-2.17 (m, 2H), 2.07-1.98 (m,1H), 1.96-1.85 (m, 2H), 1.48-1.42 (m, 2H), 1.13-1.01 (m, 1H), 0.49-0.42(m, 2H), 0.26- 0.20 (m, 2H) 382 I-387 NX GF 936.4 10.92 (s, 1H), 9.99(s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.20 (s, 1H), 8.17 (d, J = 5.6 Hz,1H), 7.82 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.43- 7.16 (m,2H), 7.13-7.08 (m, 2H), 7.05 (d, J = 5.2 Hz, 1H), 6.69-6.63 (m, 2H),6.26-6.19 (m, 1H), 6.22 (d, J = 7.6 Hz, 1H), 5.00 (dd, J = 5.2, 13.2 Hz,1H), 4.26-4.10 (m, 2H), 3.81 (s, 2H), 3.64-3.48 (m, 8H), 3.26-3.24 (m,2H), 3.22-3.15 (m, 2H), 2.94-2.90 (m, 1H), 2.88-2.82 (m, 3H), 2.74- 2.86(m, 2H), 2.61-2.58 (m, 1H), 2.57- 2.55 (m, 1H), 2.15-2.11 (m, 2H),1.91-1.89 (m, 3H), 1.41-1.38 (m, 2H), 1.10-1.06 (m, 1H), 0.49-0.44 (m,2H), 0.26-0.21 (m, 2H) 383 I-388 JZ GF 906.4 11.03 (s, 1H), 9.95 (s,1H), 8.96 (s, 1H), 8.79 (s, 1H), 8.22 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H),7.81 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.8 Hz,2H), 7.44-7.14 (m, 1H), 7.12 (s, 1H), 7.09-7.05 (m, 1H), 7.04 (d, J =6.4 Hz, 1H), 6.99-6.95 (m, 2H), 6.89-6.84 (m, 1H), 5.07-4.98 (m, 1H),3.81 (s, 2H), 3.55-3.47 (m, 6H), 3.42-3.35 (m, 1H), 3.21-3.18 (m, 2H),2.89-2.80 (m, 3H), 2.72- 2.67 (m, 2H), 2.60-2.54 (m, 1H), 2.54- 2.53 (m,1H), 2.21-2.14 (m, 2H), 2.03-1.96 (m, 1H), 1.94-1.86 (m, 2H), 1.46-1.38(m, 2H), 1.12-1.04 (m, 1H), 0.48-0.44 (m, 2H), 0.25- 0.21 (m, 2H) 384I-389 KA GF 994.6 11.04 (s, 1H), 9.98 (s, 1H), 8.95 (s, 1H), 8.78 (s,1H), 8.29 (s, 1H), 8.15 (d, J = 5.6 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H),7.57-7.44 (m, 3H), 7.43-7.15 (m, 1H), 7.11 (s, 1H), 7.09-7.01 (m, 2H),7.00-6.90 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 5.01 (dd, J = 5.2, 12.8 Hz,1H), 3.56-3.45 (m, 16H), 3.21-3.15 (m, 2H), 2.90-2.78 (m, 3H), 2.71 (t,J = 5.6 Hz, 2H), 2.62-2.54 (m, 2H), 2.26-2.03 (m, 3H), 2.02-1.95 (m,1H), 1.92-1.82 (m, 2H), 1.47-1.35 (m, 2H), 1.09-1.04 (m, 1H), 0.41- 0.50(m, 2H), 0.27-0.18 (m, 2H) 385 I-390 NY GF 892.1 11.07 (s, 1H), 9.96 (s,1H), 8.97 (s, 1H), 8.78 (s, 1H), 8.24 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H),7.80 (d, J = 8.4 Hz, 2H), 7.70-7.64 (m, 1H), 7.52 (s, 1H), 7.46-7.33 (m,1H), 7.31-7.24 (m, 1H), 7.18-7.10 (m, 1H), 7.09-7.04 (m, 1H), 5.08 (dd,J = 5.2, 13.0 Hz, 1H), 3.81 (s, 2H), 3.59 (s, 1H), 3.27- 3.19 (m, 3H),2.73-2.71 (m, 1H), 2.69- 2.67 (m, 1H), 2.61 (s, 4H), 2.58- 2.54 (m, 4H),2.06-1.99 (m, 1H), 1.12- 1.04 (m, 1H), 0.50-0.44 (m, 2H), 0.27-0.18 (m,2H) 386 I-391 KB GF 980.5 11.06 (s, 1H), 9.95 (s, 1H), 8.96 (s, 1H),8.78 (s, 1H), 8.29 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.67 (dd, J = 7.2, 8.3 Hz, 1H), 7.48 (d, J = 8.8 Hz, 2H),7.43-7.15 (m, 3H), 7.11 (s, 1H), 7.07 (t, J = 5.6 Hz, 1H), 7.03 (dd, J =1.2, 5.2 Hz, 1H), 5.08 (dd, J = 5.6, 12.8 Hz, 1H), 3.77 (s, 2H),3.57-3.46 (m, 14H), 3.27 (s, 4H), 3.19 (t, J = 6.0 Hz, 2H), 2.92- 2.81(m, 1H), 2.67 (t, J = 5.6 Hz, 2H), 2.62-2.58 (m, 4H), 2.54-2.52 (m, 2H),2.06-1.99 (m, 1H), 1.12-1.03 (m, 1H), 0.48-0.43 (m, 2H), 0.25- 0.21 (m,2H) 387 I-392 KE GF 922.7 10.93 (s, 1H), 9.98 (s, 1H), 8.97 (s, 1H),8.78 (s, 1H), 8.20 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.50 (d, J = 8.8 Hz, 3H), 7.43- 7.14 (m, 1H), 7.13-7.07 (m,2H), 7.04- 7.00 (m, 3H), 5.09-4.96 (m, 1H), 4.33-4.17 (m, 2H), 3.79 (s,2H), 3.55- 3.51 (m, 6H), 3.25-3.23 (m, 8H), 3.20-2.18 (m, 2H), 2.94-2.84(m, 1H), 2.72-2.68 (m, 2H), 2.61-2.56 (m, 1H), 2.56-2.54 (m, 4H), 2.41-2.34 (m, 1H), 2.00-1.86 (m, 1H), 1.13- 1.00 (m, 1H), 0.48-0.42 (m, 2H),0.26-0.20 (m, 2H) 388 I-393 KF GF 892.5 11.06 (s, 1H), 9.95 (s, 1H),8.96 (s, 1H), 8.78 (s, 1H), 8.22 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.81(d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H),7.44-7.14 (m, 3H), 7.12 (s, 1H), 7.10-7.00 (m, 2H), 5.06 (dd, J = 5.2,12.8 Hz, 1H), 3.83 (s, 2H), 3.60-3.47 (m, 4H), 3.44-3.35 (m, 4H), 3.19(t, J = 6.0 Hz, 2H), 2.94- 2.80 (m, 1H), 2.72 (t, J = 5.6 Hz, 2H),2.60-2.52 (m, 8H), 2.04-1.97 (m, 1H), 1.12-1.01 (m, 1H), 0.50- 0.38 (m,2H), 0.29-0.17 (m, 2H) 389 I-394 NZ GF 980.5 11.06 (s, 1H), 9.98 (s,1H), 8.96 (s, 1H), 8.78 (s, 1H), 8.35-8.32 (m, 1H), 8.32 (s, 1H), 8.15(d, J = 5.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H),7.52-7.45 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.45-7.14 (m, 3H),7.13-7.02 (m, 3H), 5.06 (dd, J = 5.2, 12.8 Hz, 1H), 3.77 (s, 2H), 3.59-3.27 (m, 18H), 3.18 (t, J = 6.0 Hz, 2H), 2.95-2.83 (m, 1H), 2.73-2.63(m, 2H), 2.62-2.51 (m, 6H), 2.07-1.96 (m, 1H), 1.10-1.03 (m, 1H), 0.50-0.40 (m, 2H), 0.26-0.15 (m, 2H) 390 I-395 KK GC 943.5 10.86 (s, 1H),10.74 (s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.01 (s, 3H), 7.93 (d, J =5.2 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H),7.33-7.28 (m, 3H), 6.88 (s, 2H), 6.79-6.75 (m, 2H), 5.97 (d, J = 8.0 Hz,1H), 4.81 (dd, J = 5.2, 12.8 Hz, 1H), 3.90 (s, 9H), 3.64 (s, 2H),3.34-3.30 (m, 3H), 2.95 (t, J = 6.0 Hz, 3H), 2.69-2.60 (m, 1H),2.58-2.51 (m, 5H), 2.39-2.31 (m, 1H), 1.97 (t, J = 10.4 Hz, 2H), 1.82-1.76 (m, 1H), 1.65 (d, J = 10.4 Hz, 2H), 1.25-1.18 (m, 2H), 0.86-0.79(m, 1H), 0.24-0.19 (m, 2H), 0.01- 0.03 (m, 2H) 391 I-396 KL GC 929.511.10 (s, 1H), 10.98 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.17 (d, J =5.2 Hz, 1H), 8.04 (s, 1H), 7.96 (d, J = 8.4 Hz, 2H), 7.74 (s, 1H),7.70-7.63 (m, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 7.6, 18.4 Hz,2H), 7.16 (t, J = 5.2 Hz, 1H), 7.12 (s, 1H), 7.00 (dd, J = 1.2, 5.2 Hz,1H), 5.08 (dd, J = 5.2, 12.8 Hz, 1H), 3.94 (s, 2H), 3.62-3.53 (m, 8H),3.30-3.21 (m, 4H), 3.19 (t, J = 6.0 Hz, 2H), 2.93-2.86 (m, 1H), 2.84 (t,J = 5.2 Hz, 2H), 2.64-2.52 (m, 8H), 2.07- 1.98 (m, 1H), 1.14-1.02 (m,1H), 0.49-0.43 (m, 2H), 0.26-0.20 (m, 2H) 392 I-397 JI KM 842.411.23-10.96 (m, 2H), 9.00 (s, 2H), 8.22 (s, 1H), 8.16 (d, J = 5.2 Hz,1H), 8.13-8.00 (m, 3H), 7.89-7.65 (m, 4H), 7.60 (s, 2H), 7.16 (t, J =5.6 Hz, 1H), 7.12 (s, 1H), 7.00 (dd, J = 1.2, 5.2 Hz, 1H), 5.14 (dd, J =4.4, 12.8 Hz, 1H), 3.89-3.65 (m, 4H), 3.19 (t, J = 6.0 Hz, 2H), 2.98 (s,3H), 2.94-2.82 (m, 3H), 2.72 (s, 2H), 2.64-2.52 (m, 2H), 2.09-2.01 (m,1H), 1.94-1.67 (m, 1H), 1.92-1.66 (m, 1H), 1.11- 1.01 (m, 1H), 0.48-0.41(m, 2H), 0.25- 0.19 (m, 2H) 393 I-398 LR GC 902.5 10.75 (s, 1H), 8.75(s, 1H), 8.67 (s, 1H), 8.05 (s, 2H), 7.93 (d, J = 5.2 Hz, 1H), 7.79 (s,1H), 7.67 (d, J = 8.8 Hz, 2H), 7.48 (s, 1H), 7.37-7.29 (m, 1H), 7.25 (d,J = 8.8 Hz, 2H), 6.92 (t, J = 5.2 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J =8.8 Hz, 1H), 6.77 (d, J = 6.8 Hz, 2H), 4.80 (dd, J = 5.2, 12.8 Hz, 1H),3.52 (s, 2H), 3.24-3.21 (m, 6H), 2.98-2.92 (m, 2H), 2.70-2.59 (m, 1H),2.45- 2.42 (m, 1H), 2.38-2.30 (m, 5H), 2.11- 2.08 (m, 1H), 1.82-1.74 (m,1H), 1.59-1.38 (m, 8H), 0.88-0.79 (m, 1H), 0.26-0.18 (m, 2H), 0.02-0.03(m, 2H) 394 I-399 KS GC 844.4 10.99 (s, 1H), 8.99 (s, 1H), 8.91 (s, 1H),8.24 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H), 7.92 (d, J = 8.4Hz, 2H), 7.73 (s, 1H), 7.59-7.49 (m, 3H), 7.17 (t, J = 5.6 Hz, 1H), 7.12(s, 1H), 7.08-6.96 (m, 3H), 6.63 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 5.6,12.8 Hz, 1H), 3.85 (s, 2H), 3.49-3.40 (m, 4H), 3.33 (q, J = 6.4 Hz, 2H),3.19 (t, J = 6.0 Hz, 2H), 2.93-2.81 (m, 1H), 2.71-2.65 (m, 2H),2.57-2.51 (m, 2H), 2.09- 1.97 (m, 1H), 1.84-1.71 (m, 4H), 1.12- 1.01 (m,1H), 0.49-0.42 (m, 2H), 0.25-0.21 (m, 2H) 395 I-400 OK KT 902.411.34-11.04 (m, 1H), 10.96 (s, 1H), 9.04 (s, 1H), 8.92 (s, 1H), 8.61 (d,J = 4.4 Hz, 1H), 8.28 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 2.8 Hz, 1H),7.89 (d, J = 8.8 Hz, 2H), 7.73 (t, J = 6.4 Hz, 1H), 7.60-7.53 (m, 1H),7.48 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 7.22-7.17 (m, 1H), 7.13 (d, J =8.8 Hz, 1H), 7.03 (d, J = 6.8 Hz, 1H), 6.61 (s, 1H), 5.10- 5.00 (m, 1H),4.31-4.22 (m, 2H), 3.78 (s, 2H), 3.66-3.51 (m, 10H), 2.88 (d, J = 4.8Hz, 3H), 2.71-2.68 (m, 1H), 2.66-2.57 (m, 1H), 2.57-2.53 (m, 1H),2.53-2.52 (m, 2H), 2.05-1.97 (m, 1H) 396 I-401 HQ KVd 881.5 11.09 (s,1H), 9.99 (s, 1H), 8.97 (s, 1H), 8.77 (s, 1H), 8.23-8.14 (m, 2H), 7.79(d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.44-7.15 (m, 1H), 7.13-7.07 (m, 2H), 7.05 (d, J = 5.2 Hz, 1H), 6.95 (d, J = 6.0 Hz, 2H), 6.86(dd, J = 2.8, 6.0 Hz, 1H), 5.36 (dd, J = 5.2, 12.6 Hz, 1H), 3.89-3.83(m, 1H), 3.55 (s, 9H), 3.23-3.15 (m, 2H), 2.99- 2.83 (m, 1H), 2.99-2.81(m, 5H), 2.76- 2.57 (m, 5H), 2.03-1.95 (m, 1H), 1.86-1.77 (m, 2H), 1.30(d, J = 6.8 Hz, 3H), 1.12-1.04 (m, 1H), 0.49- 0.42 (m, 2H), 0.25-0.23(m, 2H) 397 I-402 OK KY 903.4 11.13 (s, 1H), 9.97 (s, 1H), 8.93 (s, 1H),8.58 (s, 1H), 8.28-8.20 (m, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.63-7.53 (m,2H), 7.42 (d, J = 8.4 Hz, 2H), 7.28- 7.22 (m, 2H), 7.13 (d, J = 8.8 Hz,1H), 7.03 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 5.2 Hz, 1H), 5.05 (dd, J =5.2, 13.2 Hz, 1H), 4.29-4.20 (m, 2H), 3.76 (s, 2H), 3.65-3.62 (m, 2H),3.60-3.50 (m, 10H), 2.92-2.86 (m, 1H), 2.75 (t, J = 7.2 Hz, 2H),2.71-2.68 (m, 2H), 2.64-2.56 (m, 1H), 2.56-2.54 (m, 1H), 2.04-1.98 (m,1H), 1.87-1.80 (m, 2H) 398^(c) I-403 LB LE 893.5 11.17 (s, 1H), 9.96 (s,1H), 8.95 (s, 1H), 8.75 (s, 1H), 8.16 (d, J = 4.8 Hz, 1H), 7.75 (d, J =8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.42-7.13 (m, 1H), 7.12-6.84 (m,6H), 5.40-5.30 (m, 1H), 3.54 (s, 3H), 3.50-3.44 (m, 8H), 3.23-3.15 (m,2H), 2.98-2.94 (m, 2H), 2.89-2.82 (m, 1H), 2.65-2.55 (m, 4H), 2.04-1.95(m, 1H), 1.86- 1.79 (m, 2H), 1.12-1.04 (m, 1H), 1.03- 0.83 (m, 4H),0.53-0.40 (m, 2H), 0.26-0.18 (m, 2H) 399 I-404 LF GF 837.5 11.07 (s,1H), 9.96 (s, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.16 (d, J= 5.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.28(t, J = 52 Hz, 1H), 7.12 (s, 1H), 7.09-7.02 (m, 2H), 6.97-6.91 (m, 2H),6.84 (dd, J = 3.2, 5.6 Hz, 1H), 5.35 (dd, J = 5.2, 12.8 Hz, 1H), 3.82(s, 2H), 3.54 (s, 3H), 3.47-3.45 (m, 4H), 3.21-3.17 (m, 2H), 2.95-2.90(m, 2H), 2.88- 2.83 (m, 1H), 2.75-2.68 (m, 1H), 2.66 (d, J = 7.2 Hz,2H), 2.63-2.56 (m, 1H), 2.03-1.95 (m, 1H), 1.86-1.77 (m, 2H), 1.74-1.69(m, 2H), 1.13- 1.02 (m, 1H), 0.49-0.43 (m, 2H), 0.25- 0.20 (m, 2H) 400I-405 LG GF 836.4 10.84 (s, 1H), 9.75 (s, 1H), 8.73 (s, 1H), 8.54 (s,1H), 8.06 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H),7.26 (d, J = 8.8 Hz, 2H), 7.18- 6.89 (m, 1H), 6.89-6.87 (m, 1H), 6.86-6.79 (m, 2H), 6.79-6.72 (m, 2H), 6.61 (dd, J = 1.2, 8.0 Hz, 1H), 5.09(dd, J = 5.2, 12.8 Hz, 1H), 3.54 (s, 2H), 3.24-3.18 (m, 8H), 2.98-2.91(m, 2H), 2.72-2.60 (m, 1H), 2.52- 2.45 (m, 1H), 2.42-2.33 (m, 5H), 1.80-1.73 (m, 1H), 1.61-1.53 (m, 2H), 1.48-1.44 (m, 2H), 0.88-0.80 (m, 1H),0.26-0.19 (m, 2H), 0.03-−0.04 (m, 2H) 401 I-406 LH GF 895.5 11.10 (s,1H), 10.01 (s, 1H), 8.98 (s, 1H), 8.80 (s, 1H), 8.21 (s, 1H), 8.17 (d, J= 4.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.45-7.15 (m, 1H), 7.14-7.08 (m, 2H), 7.06- 7.03 (m, 1H), 6.98-6.93 (m, 2H),6.88-6.83 (m, 1H), 5.40-5.33 (m, 1H), 3.82 (s, 2H), 3.56 (s, 3H), 3.45-3.41 (m, 8H), 3.22-3.13 (m, 2H), 2.96- 2.90 (m, 2H), 2.90-2.84 (m, 1H),2.76-2.70 (m, 1H), 2.66-2.60 (m, 2H), 2.60-2.55 (m, 1H), 2.04-1.92 (m,1H), 1.86-1.77 (m, 2H), 1.76- 1.68 (m, 4H), 1.13-1.00 (m, 1H), 0.49-0.44 (m, 2H), 0.25-0.21 (m, 2H) 402 I-407 LI GF 895.5 11.06 (s, 1H),10.02 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.29 (s, 1H), 8.15 (d, J =5.2 Hz, 1H), 7.85-7.76 (m, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.43-7.15 (m,1H), 7.11 (s, 1H), 7.08 (t, J = 5.2 Hz, 1H), 7.05-7.02 (m, 1H), 7.02-6.95 (m, 2H), 6.85 (d, J = 7.6 Hz, 1H), 5.32 (dd, J = 5.2, 12.8 Hz, 1H),3.89 (s, 2H), 3.42-3.32 (m, 8H), 3.31 (s, 3H), 3.18 (t, J = 6.0 Hz, 2H),2.95-2.83 (m, 1H), 2.74-2.58 (m, 6H), 2.04-1.94 (m, 1H), 1.84-1.65 (m,6H), 1.11- 1.01 (m, 1H), 0.49-0.41 (m, 2H), 0.22 (g, J = 4.8 Hz, 2H) 403I-408 4-[2-[2-[2-(2- LS 827.5 11.08 (s, 1 H), 10.09 (s, 1 H), 8.92 (s, 1aminoethoxy)- H), 8.88 (s, 2 H), 8.23 (d, J = 5.2 Hz, 1 ethoxy]ethoxy]-H), 8.03 (s, 1 H), 7.63-7.55 (m, 2 H), ethylamino]- 7.24-7.21 (m, 2 H),7.11 (d, J = 8.8 2-(2,6-dioxo- Hz, 1 H), 7.03 (d, J = 6.8 Hz, 1 H),3-piperidyl)- 6.56 (s, 1 H), 5.06-5.01 (m, 1 H ), isoindoline- 4.30-4.13(m, 5 H), 3.87 (s, 2 H), 3.70- 1,3-dione 3.67 (m, 3 H), 3.60-3.57 (m, 3H), (synthesized 3.54-3.52 (m, 4 H), 3.46-3.36 (m, 3 via Steps 1-2 H),3.18 (m, 2 H), 2.94-2.83 (m, 1 H), of Example 2.63-2.53 (m, 2 H),2.05-1.96 (m, 1 128) H) 404 I-409 4-[2-[3-(2- GC 874.3 10.99 (s, 1 H),8.99 (s, 1 H), 8.94- aminoethoxy)- 8.89 (m, 1H), 8.23 (s, 1H), 8.16 (d,J = propoxy]- 5.2 Hz, 1H), 8.03 (s, 1H), 7.90 (d, J = ethylamino]- 8.4Hz, 2H), 7.72 (s, 1H), 7.59-7.54 2-(2,6-dioxo- (m, 1H), 7.48 (d, J = 8.4Hz, 2H), 7.19- 3-piperidyl)- 7.11 (m, 3H), 7.05-6.98 (m, 2H),isoindoline- 6.59 (m, 1H), 5.05 (m, 1H), 3.78 (s, 1,3-dione 2H),3.59-3.54 (m, 11H), 3.19 (m, (synthesized 2H), 2.92-2.83 (m, 1H), 2.67(m, 2 via Steps 1-2 H), 2.61-2.55 (m, 2 H), 2.06-1.98 of Example (m, 1H), 1.74 (t, J = 6.36 Hz, 2 H), 208, 1-213) 1.11-1.03 (m, 1 H),0.46-0.43 (m, 2 H), 0.23-0.22 (m, 2 H) 405 I-410 LN GF 865.5 11.09 (s,1H), 10.03 (s, 1H), 8.96 (s, 1H), 8.80 (s, 1H), 8.28 (s, 1H), 8.15 (d, J= 5.2 Hz, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 7.6 Hz, 2H), 7.42-7.15 (m, 1H), 7.11 (s, 1H), 7.08 (t, J = 5.2 Hz, 1H), 7.05-7.03 (m, 1H),7.00- 6.91 (m, 2H), 6.88-6.83 (m, 1H), 5.35 (dd, J = 5.2, 12.4 Hz, 1H),3.95- 3.91 (m, 2H), 3.54 (s, 3H), 3.41-3.38 (m, 2H), 3.36-3.32 (m, 2H),3.18 (t, J = 5.6 Hz, 2H), 2.92-2.87 (m, 2H), 2.87-2.83 (m, 1H),2.71-2.68 (m, 2H), 2.65-2.58 (m, 2H), 2.03-1.94 (m, 1H), 1.64-1.50 (m,8H), 1.11- 1.02 (m, 1H), 0.48-0.41 (m, 2H), 0.22 (q, J = 4.4 Hz, 2H) 406I-411 OD GF 865.6 11.08 (s, 1H), 10.01 (s, 1H), 8.97 (s, 1H), 8.80 (s,1H), 8.27 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H),7.52 (d, J = 8.0 Hz, 2H), 7.43- 7.15 (m, 1H), 7.14-7.07 (m, 2H), 7.06-6.96 (m, 3H), 6.85 (d, J = 8.0 Hz, 1H), 5.41-5.25 (m, 1H), 3.76 (s, 2H),3.78-3.69 (m, 1H), 3.83 (s, 2H), 3.35- 3.33 (m, 2H), 3.31 (s, 3H), 3.21-3.15 (m, 2H), 2.91-2.82 (m, 1H), 2.75- 2.68 (m, 1H), 2.64-2.58 (m, 5H),2.02-1.95 (m, 1H), 1.66-1.55 (m, 2H), 1.54-1.47 (m, 6H), 1.13-0.97 (m,1H), 0.48-0.41 (m, 2H), 0.25- 0.19 (m, 2H) 407 I-412 LR LS 825.2 11.10(s, 1H), 10.87 (s, 1H), 8.89 (s, 1H), 8.24 (s, 1H), 8.21 (d, J = 5.2 Hz,1H), 8.10 (s, 1H), 7.58-7.52 (m, 2H), 7.58-7.52 (m, 1H), 7.22-7.17 (m,2H), 7.07-6.98 (m, 2H), 6.62 (t, J = 5.6 Hz, 1H), 5.04 (dd, J = 5.2,12.8 Hz, 1H), 4.23 (dd, J = 6.8, 9.2 Hz, 2H), 3.92 (s, 1H), 3.95-3.90(m, 1H), 3.79 (s, 3H), 3.34-3.27 (m, 10H), 2.90- 2.84 (m, 1H), 2.65 (t,J = 7 .2 Hz, 2H), 2.62-2.58 (m, 1H), 2.58-2.54 (m, 1H), 2.06-1.97 (m,1H), 1.82 (t, J = 6.8 Hz, 2H), 1.80-1.72(m, 2H), 1.68- 1.60 (m, , 2H)408 I-413 LP LS 984.3 10.83 (s, 1H), 8.97 (s, 1H), 8.90 (s, 1H), 8.56(s, 1H), 8.22 (s, 2H), 8.10 (s, 1H), 7.56 (s, 1H), 7.40 (s, 5H), 7.21(s, 2H), 4.58-4.49 (m, 1H), 4.43-4.36 (m, 1H), 4.34 (s, 1H), 4.26-4.24(m, 2H), 3.95 (s, 2H), 3.85-3.75 (m, 1H), 3.79 (s, 3H), 3.70-3.58 (m,14H), 3.20- 3.16 (m, 1H), 3.07 (s, 2H), 3.15- 2.98 (m, 1H), 2.77 (s,2H), 2.64-2.59 (m, 1H), 2.48-2.40 (m, 4H), 1.93- 1.89 (m, 1H), 0.89 (s,9H) 409 I-414 LO GY 1103.2 11.01 (s, 1H), 9.02 (s, 1H), 8.97 (s, 1H),8.92 (s, 1H), 8.61 (t, J = 6.0 Hz, 1H), 8.29-8.19 (m, 2H), 8.04 (s, 1H),7.92 (d, J = 8.4 Hz, 2H), 7.78-7.63 (m, 2H), 7.50 (br d, J = 8.4 Hz,2H), 7.46-7.35 (m, 5H), 7.26 (s, 1H), 7.17 (dd, J = 1.2, 5.2 Hz, 1H),4.56 (d, J = 9.6 Hz, 1H), 4.49-4.34 (m, 3H), 4.32- 4.16 (m, 4H), 3.96(s, 2H), 3.82 (s, 2H), 3.56-3.44 (m, 11H), 2.70 (J = 6.0 Hz, 2H), 2.43(s, 3H), 2.11-2.01 (m, 1H), 1.93-1.86 (m, 1H), 0.93 (s, 9H) 410 I-415 LPGY 1089.2 11.00 (s, 1H), 9.01 (s, 1H), 8.98-8.95 (m, 1H), 8.93 (s, 1H),8.56 (t, J = 6.0 Hz, 1H), 8.33-8.17 (m, 3H), 8.04 (s, 1H), 7.98-7.88 (m,2H), 7.77-7.63 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.43- 7.34 (m, 4H),7.26 (s, 1H), 7.17 (dd, J = 1.2, 5.2 Hz, 1H), 4.57-4.18 (m, 6H),4.05-3.78 (m, 2H), 3.50-3.34 (m, 14H), 3.24-3.13 (m, 1H), 3.08 (s, 1H),2.77-2.72 (m, 2H), 2.64-2.58 (m, 1H), 2.55-2.52 (m, 1H), 2.44- 2.42 (m,3H), 2.10-2.00 (m, 1H), 1.97- 1.86 (m, 1H), 0.93-0.84 (m, 9H) 411 I-416OE GF 1233.7 9.96 (s, 1H), 8.96 (s, 1H), 8.79 (s, 1H), 8.22-8.13 (m,2H), 7.81 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.44- 7.42 (m,1H), 7.32-6.90 (m, 10H), 6.83-6.74 (m, 2H), 5.12-4.63 (m, 5H), 4.07-4.01(m, 2H), 3.87-3.81 (m, 4H), 3.74-3.71 (m, 2H), 3.58- 3.49 (m, 20H), 3.29(s, 3H), 3.20-3.17 (m, 2H), 3.06-2.90 (m, 2H), 2.75- 2.65 (m, 2H),1.90-1.49 (m, 4H), 1.03 (s, 7H), 0.94 (s, 3H), 0.51-0.41 (m, 2H),0.24-0.20 (m, 2H) 412 I-417 LY GF 1145.2 9.99 (s, 1H), 8.97 (s, 1H),8.78 (s, 1H), 8.22-8.17 (m, 1H), 8.17-8.13 (m, 1H), 7.80-7.76 (m, 2H),7.52-6.72 (m, 15H), 5.08-4.96 (m, 1H), 4.92- 4.58 (m, 4H), 4.12 (s, 2H),3.90-3.81 (m, 2H), 3.77-3.71 (m, 4H), 3.56- 3.50 (m, 9H), 3.31-3.27 (m,5H), 3.20- 3.16 (m, 2H), 3.09-2.91 (m, 3H), 2.69-2.64 (m, 3H), 1.89-1.51(m, 4H), 1.12 (s, 9H), 0.49-0.42 (m, 2H), 0.25-0.20 (m, 2H) 413 I-418 LXGF 1189.7 9.75 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.13 (s, 1H),7.99-7.91 (m, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.27-7.18 (m, 4H), 7.06 (s,1H), 6.91-6.79 (m, 9H), 6.69 (d, J = 2.3 Hz, 1H), 6.59-6.52 (m, 2H),4.79 (d, J = 9.4 Hz, 1H), 4.69- 4.61 (m, 2H), 4.47-4.36 (m, 2H), 3.82(s, 2H), 3.67-3.59 (m, 2H), 3.54- 3.48 (m, 5H), 3.36-3.29 (m, 6H), 2.99-2.92 (m, 4H), 2.46-2.39 (m, 5H), 2.12-2.07 (m, 1H), 1.65-1.48 (m, 3H),1.43-1.31 (m, 2H), 0.73-0.65 (m, 2H), 0.25-0.19 (m, 2H), 0.02-−0.03 (m,2H) 414 I-419 LZ GF 923.5 11.07 (s, 1H), 9.96 (s, 1H), 8.96 (s, 1H),8.77 (s, 1H), 8.29 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 8.8Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.42- 7.15 (m, 1H), 7.12 (s, 1H),7.08 (t, J = 5.6 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 6.99-6.90 (m, 2H),6.87-6.81 (m, , 1H), 5.35 (dd, J = 5.2, 12.4 Hz, 1H), 3.75 (s, 2H), 3.56(s, 3H), 3.44-3.42 (m, 2H), 3.19 (t, J = 6.4, 2H), 3.12 (d, J = 2.0 Hz,4H), 2.98-2.90 (m, 2H), 2.89-2.84 (m, 1H), 2.67-2.56 (m, 6H), 2.03-1.94(m, 1H), 1.83-1.75 (m, 2H), 1.72-1.64 (m, 2H), 1.10- 1.03 (m, 1H), 0.84(s, 6H), 0.48-0.43 (m, 2H), 0.23 (q, J = 4.8 Hz, 2H) 415 I-420 LZ LS839.4 11.08 (s, 1H), 10.93 (s, 1H), 8.86 (s, 1H), 8.27 (s, 1H), 8.20 (d,J = 4.8 Hz, 1H), 8.10 (s, 1H), 7.53 (t, J = 6.4 Hz, 1H), 7.21-7.13 (m,2H), 7.00-6.88 (m, 2H), 6.83-6.75 (m, 1H), 5.35 (dd, J = 5.6, 12.4 Hz,1H), 4.26-4.19 (m, 2H), 3.90 (s, 2H), 3.76 (s, 3H), 3.51 (s, 3H),3.46-3.42 (m, 4H), 2.98 (d, J = 7.2 Hz, 4H), 2.91-2.83 (m, 3H), 2.65-2.58 (m, 4H), 2.04-1.95 (m, 1H), 1.88-1.79 (m, 2H), 1.77-1.69 (m, 2H),0.71 (s, 6H) 416 I-421 MA GF 923.5 11.08 (s, 1H), 10.19 (s, 1H), 9.33-9.23 (m, 2H), 9.14 (s, 1H), 8.87 (s, 1H), 8.11 (d, J = 6.4 Hz, 1H), 7.95(d, J = 7.6 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.57 (s, 1H), 7.48-7.19(m, 1H), 7.27-7.17 (m, 1H), 7.02 (s, 2H), 6.85 (d, J = 8.0 Hz, 1H),5.42-5.30 (m, 1H), 4.20 (s, 2H), 3.45-3.43 (m, 6H), 3.32 (s, 3H), 3.14(s, 2H), 3.09 (s, 2H), 3.01-2.93 (m, 2H), 2.92-2.85 (m, 1H), 2.72-2.65(m, 2H), 2.62-2.57 (m, 1H), 2.57-2.55 (m, 1H), 2.57- 2.55 (m, 1H),1.96-1.88 (m, 1H), 1.96- 1.88 (m, 2H), 1.86-1.74 (m, 2H), 1.20-1.10 (m,1H), 0.85 (s, 6H), 0.60- 0.53 (m, 2H), 0.36-0.30 (m, 2H) 417^(c) I-422HQ MB 714.3 11.08 (s, 1H), 10.88 (s, 1H), 8.98 (s, 2H), 8.88 (s, 1H),8.66 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H), 8.01 (s, 1H), 7.81 (s, 1H), 7.67(d, J = 8.8 Hz, 2H), 6.99- 6.92 (m, 2H), 6.86-6.83 (m, 1H), 5.41- 5.30(m, 1H), 4.26 (s, 2H), 3.74- 3.70 (m, 2H), 3.66-3.60 (m, 2H), 3.60- 3.57(m, 2H), 3.55 (s, 3H), 3.50- 3.46 (m, 2H), 3.16 (s, 2H), 2.99-2.91 (m,2H), 2.90-2.81 (m, 1H), 2.76- 2.68 (m, 1H), 2.68-2.62 (m, 1H), 2.05-1.94 (m, 1H), 1.89-1.77 (m, 2H) 418 I-423 MG GF 779.1 11.10 (s, 1H),10.00 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.28 (s, 1H), 8.16 (d, J =5.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.45-7.15 (m, 1H), 7.12 (s, 1H), 7.09 (t, J = 5.6 Hz, 1H), 7.05 (dd, J = 1.2,5.2 Hz, 1H), 6.99-6.92 (m, 2H), 6.87 (dd, J = 2.8, 6.0 Hz, 1H), 5.36(dd, J = 5.2, 12.8 Hz, 1H), 3.81 (s, 2H), 3.58 (s, 3H), 3.19 (t, J = 6.0Hz, 2H), 2.99- 2.94 (m, 2H), 2.90-2.85 (m, 1H), 2.73- 2.68 (m, 1H),2.66-2.63 (m, 2H), 2.62-2.58 (m, 1H), 2.04-1.96 (m, 1H), 1.85-1.76 (m,2H), 1.12-1.03 (m, 1H), 0.50-0.42 (m, 2H), 0.25- 0.21 (m, 2H) ªForMethod 16, when the amine is the HCl salt, TEA was added to free basethe salt, followed by HOAc to adjust the pH to 3-4. KOAc could also beused in place of the TEA/HOAc combination. ^(b)TFA not HCl was used forthe deprotection in Step 2. ^(c)No deprotection Step 2 required.^(d)Coupling partner was a ketone not aldehyde. ^(e)Steps 1-2 was runanywhere from 0.5-48 hrs.

Further Examples Example 419:N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-(2-cyclopropyl-4-pyridyl)oxazole-4-carboxamide,I-424

N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-(2-cyclopropyl-4-pyridyl)oxazole-4-carboxamidewas synthesized via Method 10, coupling amine methyl4-(4-amino-3-carbamoyl-pyrazol-1-yl)benzoate (Intermediate CL) and acid2-(2-cyclopropyl-4-pyridyl)oxazole-4-carboxylic acid (Intermediate MQ)in Step 1, and coupling amine4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(synthesized via Steps 1-2 of Example 127) in Step 3. The final productwas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 33%-53%, 7 min) to give thetitle compound (29.0 mg, 14% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.14-11.04 (m, 2H), 9.10 (s, 1H), 9.03 (s, 1H), 8.66-8.61(m, 2H), 8.15 (s, 1H), 8.11-8.06 (m, 2H), 8.04-7.98 (m, 2H), 7.88-7.81(m, 2H), 7.69 (dd, J=1.2, 5.6 Hz, 1H), 7.58-7.52 (m, 1H), 7.11 (d, J=8.8Hz, 1H), 7.01 (d, J=6.8 Hz, 1H), 6.60 (t, J=5.6 Hz, 1H), 5.11-4.90 (m,1H), 3.64-3.53 (m, 8H), 3.49-3.40 (m, 5H), 2.92-2.83 (m, 1H), 2.68-2.53(m, 1H), 2.34-2.26 (m, 2H), 2.15-1.89 (m, 2H), 1.07-0.96 (m, 4H). LC-MS(ESI⁺) m/z 845.2 (M+H)⁺.

Example 420:4-[2-[4-[2-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]ethynyl]-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide,I-425

Step1-2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-(4-iodophenoxy)ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of2-[2-[2-[2-(4-iodophenoxy)ethoxy]ethoxy]ethoxy]ethanamine (800 mg, 1.85mmol, HCl, Intermediate FJ) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (511 mg, 1.85mmol, Intermediate R) in dioxane (10 mL) was added DIPEA (1.20 g, 9.27mmol, 1.61 mL), and the reaction mixture was stirred at 115° C. for 16hr. On completion, the mixture was concentrated in vacuo to give aresidue. The residue was purified by column chromatography to give thetitle compound (900 mg, 75% yield) as yellow solid. LC-MS (ESI⁺) m/z652.3 (M+H)⁺.

Step2-2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-[4-(2-trimethylsilylethynyl)phenoxy]ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-[2-(4-iodophenoxy)ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione (800 mg, 1.23 mmol), Pd(PPh₃)₂Cl₂ (25.8mg, 36.8 umol) and CuI (7.02 mg, 36.8 umol) in TEA (10 mL) was addedethynyl(trimethyl)silane (241 mg, 2.46 mmol, 340 Ul, CAS #1066-54-2),and the reaction mixture was stirred at 80° C. for 12 hr. On completion,the mixture was filtered and the filtrate was concentrated in vacuo togive a residue. The residue was purified by column chromatography togive the title compound (800 mg, 93% yield) as yellow oil. LC-MS (ESI⁺)m/z 622.2 (M+H)⁺.

Step3-2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-(4-ethynylphenoxy)ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione

To a solution of2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-[2-[4-(2-trimethylsilylethynyl)phenoxy]ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione (700 mg, 1.13 mmol) inTHF (10 mL) was added TBAF (883 mg, 3.38 mmol), and the reaction mixturewas stirred at 20° C. for 2 hours. On completion, the reaction mixturewas concentrated in vacuo to give a residue. The residue was purified bycolumn chromatography to give the title compound (500 mg, 810% yield) asa yellow solid. LC-MS (ESI⁺) m/z 550.3 (M+1)⁺.

Step4-4-[2-[4-[2-[2-[2-[2-[[2-(2,6-Dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]phenyl]ethynyl]-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide

To a solution of4-bromo-1-[[(2S,3S,4S)-3-ethyl-4-fluoro-5-oxo-pyrrolidin-2-yl]methoxy]-7-methoxy-isoquinoline-6-carboxamide(20.0 mg, 45.4 umol, synthesized via Steps 1-2 of Example 126), CuI(4.33 mg, 22.7 umol), Pd(PPh₃)₂Cl₂ (15.9 mg, 22.7 umol) in DMF (2 mL)was added2-(2,6-dioxo-3-piperidyl)-4-[2-[2-[2-[2-(4-ethynylphenoxy)ethoxy]ethoxy]ethoxy]ethylamino]-isoindoline-1,3-dione(50.0 mg, 90.9 umol) and TEA (82.8 mg, 818 umol, 113 uL). The reactionmixture was degassed with N₂ for 5 minutes, and then heated at 120° C.for 3 hours under microwave. On completion, the mixture was filtered andthe filtrate was concentrated in vacuo to give a residue. The residuewas dissolved in DCM (20 mL) and thiourea (resin) (50 mg) was added. Themixture was stirred at 20° C. for 2 hours. Then the reaction mixture wasfiltered and the filtrate was concentrated in vacuo to give a residue.The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 35%-65%, 10min) to give the title compound (4.19 mg, 9.85% yield) as yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 8.89 (s, 1H), 8.18 (s, 1H),7.95 (s, 1H), 7.79 (s, 2H), 7.61-7.40 (m, 4H), 7.12 (d, J=8.4 Hz, 1H),7.01 (d, J=8.0 Hz, 3H), 6.61-6.54 (m, 1H), 5.04 (dd, J=4.8, 12.4 Hz,1H), 4.99-4.82 (m, 1H), 4.60-4.52 (m, 1H), 4.30 (dd, J=5.6, 10.8 Hz,1H), 4.16-4.06 (m, 3H), 3.98 (s, 3H), 3.75-3.68 (m, 3H), 3.60-3.55 (m,12H), 2.93-2.75 (m, 1H), 2.63-2.60 (m, 1H), 2.59-2.57 (m, 1H), 2.08-1.94(m, 1H), 1.67-1.50 (m, 2H), 1.01 (t, J=7.2 Hz, 3H); LC-MS (ESI⁺) m/z909.5 (M+H)⁺.

Example 421:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[1-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethyl]isoindolin-5-yl]-3-(trifluoromethyl)pyrazol-4-yl]oxazole-4-carboxamide,I-426

To a solution of2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[1-isoindolin-5-yl-3-(trifluoromethyl)pyrazol-4-yl]oxazole-4-carboxamide (190 mg, 348 umol, HCl, synthesizedvia Method 12 coupling5-[4-amino-3-(trifluoromethyl)pyrazol-1-yl]isoindoline-2-carboxylate(Intermediate FM) and2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (from Steps 1-4 of Intermediate DF) in Step 1),2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]acetaldehyde(116 mg, 290 umol, Intermediate FK) in THF (30.0 mL) was added KOAc(56.9 mg, 580 umol) and NaBH(OAc)₃ (122 mg, 580 umol). The reactionmixture was stirred at 25° C. for 16 hours. On completion, the mixturewas diluted with H₂O (1 mL) and then concentrated in vacuo. The mixturewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 10%-40%, 10 min) to give thetitle compound (16.1 mg, 5.9% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.1 (s, 1H), 9.94 (s, 1H), 8.97 (s, 1H), 8.83 (s, 1H), 8.15(d, J=5.2 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.57 (t, J=7.8Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.17-7.08 (m, 3H), 7.06-7.00 (m, 2H),6.69-6.53 (m, 1H), 5.08-5.00 (m, 1H), 4.00-3.85 (m, 4H), 3.68-3.55 (m,6H), 3.50-3.47 (m, 4H), 3.20-3.15 (m, 2H), 2.95-2.86 (m, 1H), 2.86-2.80(m, 2H), 2.61-2.55 (m, 1H), 2.54-2.53 (m, 1H), 2.05-1.92 (m, 1H),1.08-1.00 (m, 1H), 0.49-0.43 (m, 2H), 0.25-0.20 (m, 2H); LC-MS (ESI⁺)m/z 897.4 (M+H)⁺.

Example 422:2-(2-Amino-4-pyridyl)-N-[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-427

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(50.0 mg, 54.4 umol, synthesized via Method 10, coupling acidIntermediate HI and amine Intermediate CL in Step 1, and coupling amine4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione synthesized viaSteps 1-2 of Example 127 in Step 3) in DCM (5 mL) was added HCl/dioxane(4 M, 13.6 uL). The mixture was stirred at 15° C. for 30 minutes. Oncompletion, the mixture was concentrated in vacuo. The residue waspurified by prep-HPLC (column: Luna C18 150*25 5u; mobile phase: [water(0.225% FA)-ACN]; B %: 29%-49%, 7.8 min) to give the title compound(22.0 mg, 44% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.11 (s, 1H), 11.01 (s, 1H), 9.04 (s, 1H), 9.02 (s, 1H), 8.63 (t, J=5.2Hz, 1H), 8.17-8.14 (m, 1H), 8.17-8.14 (m, 1H), 8.13 (d, J=5.6 Hz, 1H),8.11-8.06 (m, 2H), 8.05-8.00 (m, 2H), 7.80 (s, 1H), 7.59-7.54 (m, 1H),7.59-7.54 (m, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.07 (s, 1H), 7.05 (s, 1H),7.03-7.01 (m, 1H), 7.03-7.01 (m, 1H), 7.02 (d, J=7.2 Hz, 1H), 6.60 (t,J=5.6 Hz, 1H), 6.42 (s, 2H), 5.06 (dd, J=5.2, 12.8 Hz, 1H), 3.65-3.61(m, 2H), 3.61-3.55 (m, 6H), 3.48-3.43 (m, 2H), 3.43 (s, 2H), 2.92-2.85(m, 1H), 2.61 (s, 1H), 2.56 (s, 1H), 2.06-2.00 (m, 1H); LC-MS (ESI⁺) m/z820.5 (M+H)⁺.

Example 423:N-[1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-428

Tert-butylN-[4-[4-[[1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamatewas synthesized via Method 10 with methyl4-[4-amino-3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]pyrazol-1-yl]benzoate (Intermediate JT) as the amine and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (Intermediate CM) as the acid in Step 1, and4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(50.3 mg, 114 umol, HCl, synthesized via Steps 1-2 of Example 127) asthe amine in Step 3. In the final step, to a solution oftert-butylN-[4-[4-[[1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-3-[3-(2-hydroxyethyl)-2-oxo-imidazolidin-1-yl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(100 mg, 91.9 umol) in DCM (10 mL) was added HCl/dioxane (4 M, 2 mL).The mixture was stirred at 20° C. for 3 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byPre-HPLC (column: Phenomenex Synergi C18 150*30 mm*4 um; mobile phase:[water (0.225% FA)-ACN]) to give the title compound (30 mg, 33% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (s, 1H), 11.09 (s,1H), 8.97-8.93 (m, 2H), 8.54 (s, 1H), 8.25-8.24 (d, J=5.6 Hz, 1H), 7.98(d, J=8.8 Hz, 2H), 7.88 (d, J=8.8 Hz, 2H), 7.60-7.50 (m, 2H), 7.23 (d,J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 1H), 7.01 (d, J=7.2 Hz, 1H), 6.59 (s,1H), 5.05 (dd, J=5.2, 13.2 Hz, 1H), 4.95 (s, 1H), 4.27-4.24 (m, 2H),4.06-3.96 (m, 2H), 3.64-3.54 (m, 10H), 3.44-3.40 (m, 6H), 2.95-2.85 (m,1H), 2.60-2.54 (m, 2H), 2.04-2.01 (m, 1H); LC-MS (ESI⁺) m/z 987.8(M+H)⁺.

Example 424:N-[3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-429

Tert-butylN-[4-[4-[[3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamatewas synthesized via Method 10, with methyl4-[4-amino-3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)pyrazol-1-yl]benzoate(Intermediate JV) as the amine and2-[2-[tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (Intermediate CM) as the acid in Step 1, and4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(synthesized via Steps 1-2 of Example 127) as the amine in Step 3. Inthe final step, to a solution of tert-butylN-[4-[4-[[3-(3,3-dimethyl-2-oxo-pyrrolidin-1-yl)-1-[4-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(42 mg, 39.2 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 196 uL).The mixture was stirred at 20° C. for 3 hours. On completion, thereaction mixture was concentrated in vacuo. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.05% HCl)-ACN]) to give the title compound (11.6 mg, 29% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 11.08 (s,1H), 8.99 (s, 1H), 8.96 (s, 1H), 8.55 (s, 1H), 8.26 (d, J=5.2 Hz, 1H),7.98 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.78 (s, 1H), 7.55 (t,J=7.6 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=5.2 Hz, 1H), 7.11 (d, J=8.8 Hz,1H), 7.01 (d, J=7.2 Hz, 1H), 6.59 (s, 1H), 5.05 (dd, J=5.2, 13.2 Hz,1H), 4.32-4.23 (m, 2H), 3.98 (t, J=6.8 Hz, 2H), 3.64-3.54 (m, 6H),3.51-3.47 (m, 4H), 2.94-2.81 (m, 1H), 2.62-2.53 (m, 4H), 2.11 (t, J=6.8Hz, 2H), 2.02 (d, J=11.2 Hz, 1H), 1.27 (s, 6H); LC-MS (ESI⁺) m/z 970.5(M+H)⁺.

Example 427:N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-2-[2-[2-[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-3-pyridyl]oxazole-4-carboxamide,I-432

To a solution of2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethylamino]-3-pyridyl]-N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]oxazole-4-carboxamide(160 mg, 293 umol, HCl, Intermediate LW) in dioxane (20 mL) was addedDIPEA (379 mg, 2.93 mmol) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (121 mg, 440umol, Intermediate R). The mixture was stirred at 115° C. for 48 hours.On completion, the mixture was concentrated in vacuo. The residue waspurified by prep-HPLC (column: Phenomenex luna C18 150*25 10u; mobilephase: [water (0.225% FA)-ACN]; B %: 22%-52%, 10 min) to give the titlecompound (60 mg, 26% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 11.10 (s, 1H), 9.98 (s, 1H), 8.86 (s, 1H), 8.40-8.32 (m, 1H),8.26-8.22 (m, 1H), 8.18-8.12 (m, 2H), 7.60-7.49 (m, 1H), 7.25-6.98 (m,3H), 6.75-6.68 (m, 1H), 6.60-6.52 (m, 1H), 5.08-4.92 (m, 1H), 3.90 (s,3H), 3.82-3.69 (m, 2H), 3.68-3.58 (m, 2H), 3.57-3.35 (m, 12H), 2.94-2.78(m, 1H), 2.60-2.52 (m, 2H), 2.08-1.94 (M, 1H); LC-MS (ESI⁺) m/z 766.3(M+H)⁺.

Example 429:N-[3-carbamoyl-1-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]hexa-2,4-diynyl]pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide,I-434

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]hexa-2,4-diynyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of CuI (6.33 mg, 33.2 umol), TMEDA (1.38 mg, 11.87 umol)in acetone (2 mL) was added2-(2,6-dioxo-3-piperidyl)-4-[2-(2-prop-2-ynoxyethoxy)ethylamino]isoindoline-1,3-dione(118 mg, 297 umol, Intermediate MV) and tert-butylN-[4-[4-[(3-carbamoyl-1-prop-2-ynyl-pyrazol-4-yl)carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(15.0 mg, 29.7 umol, synthesized via Step 1 of of Example 299, I-304).The reaction mixture was stirred at rt for 48 hrs under an oxygenatmosphere. On completion, the mixture was concentrated in vacuo. Theresidue was purified by reverse phase (0.1% FA) to give title compound(20.0 mg, 74% yield) as a yellow solid. LC-MS (ESI⁺) m/z 903.1 (M+H)⁺.

Step2—N-[3-carbamoyl-1-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]hexa-2,4-diynyl]pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture of tert-butylN-[4-[4-[[3-carbamoyl-1-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]hexa-2,4-diynyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(20.0 mg, 22.1 umol) in DCM (2 mL) was added HC/dioxane (4 M, 5.54 uL)and the reaction mixture was stirred at rt for 0.5 hr. On completion,the mixture was concentrated in vacuo. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 15%-45%, 10 min) to give the titlecompound (2.00 mg, 14% yield, FA) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.09 (s, 1H), 10.97 (s, 1H), 8.95 (s, 1H), 8.49-8.44 (m,2H), 8.15 (d, J=5.6 Hz, 1H), 7.84 (s, 1H), 7.60-7.54 (m, 2H), 7.16-7.09(m, 3H), 7.05-6.97 (m, 2H), 6.60 (t, J=5.6 Hz, 1H), 5.35 (s, 2H), 5.05(dd, J=5.6, 13.2 Hz, 1H), 4.30 (s, 2H), 3.62-3.58 (m, 3H), 3.49-3.43 (m,2H), 3.18 (t, J=6.0 Hz, 2H), 2.94-2.81 (m, 1H), 2.69-2.65 (m, 2H),2.34-2.31 (m, 2H), 2.08-1.98 (m, 2H), 1.06 (s, 1H), 0.48-0.42 (m, 2H),0.22 (d, J=4.8 Hz, 2H); LC-MS (ESI⁺) m/z 803.3 (M+H)⁺.

Example 430:N-[3-carbamoyl-1-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]hexyl]pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide,I-435

Step 1—Tert-ButylN-[4-[4-[[1-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]hexa-2,4-diynyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of CuI (84.4 mg, 443 umol), TMEDA (18.4 mg, 158 umol) inacetone (5 mL) was added tert-butylN-[4-[4-[(3-carbamoyl-1-prop-2-ynyl-pyrazol-4-yl)carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(200 mg, 396 umol, synthesized via Step 1 of Example 299, I-304) andtert-butyl N-[2-(2-prop-2-ynoxyethoxy)ethyl]carbamate (962 mg, 3.96mmol, synthesized via Step 1 of Intermediate CQ). The reaction mixturewas stirred for 12 hours under an oxygen atmosphere. On completion, themixture was concentrated in vacuo to give the title compound (1.80 g,97% yield, HCl) as a brown solid. LC-MS (ESI⁺) m/z 747.2 (M+H)⁺.

Step2—Tert-ButylN-[4-[4-[[1-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]hexyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a mixture of tert-butylN-[4-[4-[[1-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]hexa-2,4-diynyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(160 mg, 214 umol) in THF (10 mL) was added Pd/C (428.49 umol) and thesuspension was degassed under vacuum and purged with H₂ gas 3 times. Themixture was stirred at rt for 1 hr under H₂ (15 Psi). On completion, themixture was concentrated in vacuo to give the title compound (160 mg,99% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H),9.02 (s, 1H), 8.60 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.25 (s, 1H),7.73-7.64 (m, 2H), 7.49 (s, 1H), 6.87 (s, 1H), 5.31 (s, 1H), 4.57 (t,J=5.6 Hz, 1H), 4.18 (t, J=6.8 Hz, 2H), 3.86 (d, J=6.4 Hz, 2H), 2.18 (s,1H), 1.82 (d, J=6.8 Hz, 3H), 1.46 (s, 19H), 0.91-0.82 (m, 2H), 0.41 (d,J=7.6 Hz, 2H), 0.24 (d, J=4.0 Hz, 2H), −0.06 (s, 4H).

Step3—N-[1-[6-[2-(2-aminoethoxy)ethoxy]hexyl]-3-carbamoyl-pyrazol-4-yl]-2-[2-(cyclopropylmethyl amino)-4-pyridyl]oxazole-4-carboxamide

To a mixture of tert-butylN-[4-[4-[[1-[6-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]hexyl]-3-carbamoyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(100 mg, 132 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 6.7 mL).The reaction mixture was stirred at rt for 0.5 hr. On completion, themixture was concentrated in vacuo to give the title compound (75.0 mg,95% yield, HCl) as brown oil. LC-MS (ESI⁺) m/z 555.2 (M+H)⁺.

Step4—N-[3-carbamoyl-1-[6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]hexyl]pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide

To a mixture ofN-[1-[6-[2-(2-aminoethoxy)ethoxy]hexyl]-3-carbamoyl-pyrazol-4-yl]-2-[2-(cyclopropylmethylamino)-4-pyridyl]oxazole-4-carboxamide (45.0 mg, 76.1 umol,HCl), 2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (21.0 mg,76.1 umol, Intermediate R) in DMSO (2 mL) was added DIEA (98.4 mg, 761umol). The mixture was stirred at 130° C. for 0.5 hr. On completion, themixture was concentrated in vacuo. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 23%-43%, 7 min and column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 25%-45%, 9min) to give the title compound (8.50 mg, 12% yield) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.14-11.09 (m, 1H), 11.00 (s, 1H), 9.08 (s,1H), 8.38 (s, 1H), 8.10 (d, J=6.4 Hz, 1H), 7.76 (s, 1H), 7.61-7.48 (m,3H), 7.24-7.11 (m, 2H), 7.03 (d, J=7.2 Hz, 1H), 6.60 (s, 1H), 5.10-5.00(m, 1H), 4.17 (t, J=7.2 Hz, 2H), 3.65-3.44 (m, 12H), 3.28 (d, J=6.8 Hz,4H), 2.95-2.82 (m, 1H), 2.71-2.65 (m, 1H), 2.37-2.31 (m, 1H), 2.08-1.98(m, 1H), 1.86-1.69 (m, 2H), 1.52-1.39 (m, 2H), 1.35-1.08 (m, 5H), 0.56(d, J=6.8 Hz, 2H), 0.39-0.25 (m, 2H); LC-MS (ESI⁺) m/z 811.1 (M+H)⁺.

Example 431:3-[3-Methyl-2-oxo-5-[3-[3-[4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]propoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-436)

Step 1-3-Prop-2-ynoxypropan-1-ol (3)

To a solution of propane-1,3-diol (10.0 g, 131 mmol, 9.52 mL, CAS#126-30-7) and 3-bromoprop-1-yne (15.6 g, 131 mmol, 11.3 mL, CAS#106-96-7) in THF (250 mL) was added KOH (7.37 g, 131 mmol), KI (3.27 g,19.7 mmol) and TBAI (2.91 g, 7.88 mmol). The reaction mixture wasstirred at 25° C. for 16 hrs. On completion, the mixture was filtered,and the filter was concentrated in vacuo to give a residue, the residuewas diluted with H₂O (50 mL), and then extracted with EA (2×100 mL). Theorganic phase was concentrated in vacuo to give a residue. The residuewas purified by flash silica gel chromatography to give the titlecompound (8.00 g, 53% yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ4.14 (d, J=2.4 Hz, 2H), 3.75 (t, J=5.6 Hz, 2H), 3.68 (t, J=5.6 Hz, 2H),2.44 (t, J=2.4 Hz, 1H), 2.23 (s, 1H), 1.88-1.81 (m, 2H).

Step2-3-[5-[3-(3-Hydroxypropoxy)prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(5)

To a solution of 3-prop-2-ynoxypropan-1-ol (506 mg, 4.44 mmol) and3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (500mg, 1.48 mmol, Intermediate HN) in DMSO (10 mL) was added DIEA (955 mg,7.39 mmol, 1.29 mL), CuI (56.3 mg, 295 umol) and Pd(PPh₃)₂Cl₂ (207 mg,295 umol). The reaction mixture was stirred at 80° C. for 2 hr under N₂.On completion, the mixture was filtered; the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phasecolumn (0.1% FA condition) to give the title compound (370 mg, 67%yield) as a yellow solid. LC-MS (ESI⁺) m/z 372.1 (M+H)⁺.

Step3-3-[5-[3-(3-Hydroxypropoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(6)

To a solution of3-[5-[3-(3-hydroxypropoxy)prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (370 mg, 996 umol) in THF (20 mL) was added Pd/C(100 mg, 10% purity) and Pd(OH)₂/C (100 mg, 10% purity). The reactionmixture was stirred at 25° C. for 12 hrs under H₂ (15 psi). Oncompletion, the residue was filtered and the filtrate was concentratedin vacuo to give the title compound (340 mg, 90% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 7.06-6.96 (m, 2H),6.86 (d, J=8.0 Hz, 1H), 5.33 (dd, J=5.2, 12.8 Hz, 1H), 4.36 (s, 1H),3.47 (t, J=6.4 Hz, 2H), 3.43-3.40 (m, 2H), 3.37-3.34 (m, 2H), 3.34 (s,3H), 2.95-2.85 (m, 1H), 2.76-2.57 (m, 4H), 2.04-1.96 (m, 1H), 1.85-1.76(m, 2H), 1.69-1.62 (m, 2H); LC-MS (ESI⁺) m/z 376.2 (M+H)⁺.

Step4-3-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]propylmethanesulfonate (7)

To a solution of3-[5-[3-(3-hydroxypropoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(100 mg, 266 umol) and TEA (80.8 mg, 799 umol, 111 uL) in DCM (5 mL) wasadded MsCl (36.6 mg, 319 umol, 24.7 uL) at 0° C. The reaction mixturewas stirred at 20° C. for 1 hr. On completion, the mixture was quenchedby water (20 mL), and then extracted with DCM (2×50 mL). The organicphase was concentrated in vacuo to give the title compound (100 mg, 83%yield) as yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.03(s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.90-6.84 (m, 1H), 5.34 (dd, J=5.2,12.8 Hz, 1H), 4.27 (t, J=6.4 Hz, 2H), 3.47-3.43 (m, 2H), 3.38 (t, J=6.4Hz, 2H), 3.34 (m, 3H), 3.17 (s, 3H), 2.95-2.84 (m, 1H), 2.73-2.57 (m,4H), 2.04-1.96 (m, 1H), 1.94-1.88 (m, 2H), 1.86-1.78 (m, 2H); LC-MS(ESI⁺) m/z 454.2 (M+H)⁺.

Step5-3-[3-Methyl-2-oxo-5-[3-[3-[4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]propoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione.(I-436)

To a solution of3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]propylmethanesulfonate (90.4 mg, 199 umol) andN-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-amine(70.0 mg, 166 umol, Intermediate OP) in CH₃CN (10 mL) was added KI (276ug, 1.66 umol) and NaHCO₃ (41.9 mg, 498 umol). The reaction mixture wasstirred at 130° C. for 12 hrs. On completion, the residue was purifiedby prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 11%-35%, 8 min) to give the title compound(20.8 mg, 16% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.10 (s, 1H), 7.79 (s, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.08-6.97 (m, 2H),6.87 (d, J=8.0 Hz, 1H), 6.53 (d, J=2.8 Hz, 1H), 6.21 (d, J=8.0 Hz, 1H),5.34 (dd, J=5.2, 12.8 Hz, 1H), 4.12-3.99 (m, 1H), 3.94-3.86 (m, 2H),3.59-3.50 (m, 2H), 3.46-3.33 (m, 6H), 3.33 (s, 3H), 2.95-2.85 (m, 1H),2.72-2.67 (m, 1H), 2.66-2.62 (m, 2H), 2.61-2.57 (m, 1H), 2.56-2.51 (m,4H), 2.44-2.34 (m, 3H), 2.34-2.30 (m, 2H), 2.29-2.25 (m, 1H), 2.04-1.94(m, 3H), 1.88-1.73 (m, 6H), 1.70-1.61 (m, 4H), 1.51 (q, J=12.0 Hz, 2H),1.33 (q, J=11.6 Hz, 2H); LC-MS (ESI⁺) m/z 742.5 (M+H)⁺.

Example 432:3-[3-Methyl-2-oxo-5-[3-[3-oxo-3-[4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]propoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-437)

Step 1—Tert-Butyl 3-prop-2-ynoxypropanoate (3)

A mixture of tert-butyl prop-2-enoate (2 g, 15.6 mmol, 2.27 mL, CAS#1663-39-4), prop-2-yn-1-ol (2.62 g, 46.8 mmol, 2.77 mL, CAS #107-19-7)in THF (10 mL) was added NaOMe (84.3 mg, 1.56 mmol), and then themixture was stirred at 25° C. for 16 hrs under N₂ atmosphere. Oncompletion, the mixture was diluted with water (30 mL), and thenextracted with EA (2×100 mL). The organic layer was dried with Na₂SO₄,filtrated and concentrated in vacuo to give the title compound (1.80 g,63% yield) as light yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.18 (d, J=2.4Hz, 2H), 3.78 (t, J=6.4 Hz, 2H), 2.54 (t, J=6.4 Hz, 2H), 2.45 (s, 1H),1.47 (s, 9H).

Step 2—Tert-Butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]propanoate(5)

A mixture of3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (400mg, 1.18 mmol, Intermediate HN), tert-butyl 3-prop-2-ynoxypropanoate(654 mg, 3.55 mmol), Pd(PPh₃)₂Cl₂ (166 mg, 236 umol), CuI (45.0 mg, 236umol) and TEA (2.15 g, 21.0 mmol, 2.96 mL) in DMF (15 mL) was degassedand purged with N₂ for 3 times, and then the mixture was stirred at 85°C. for 4 hrs under N₂ atmosphere. On completion, the mixture was dilutedwith water (50 mL), and then extracted with EA (2×100 mL). The organiclayer was washed with brine (20 mL), dried with Na₂SO₄, filtrated andconcentrated in vacuo. The residue was purified by reverse phase flashto give the title compound (300 mg, 49% yield) as light yellow solid.LC-MS (ESI⁺) m/z 386.1 (M+1-56)⁺.

Step 3—Tert-Butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]propanoate(6)

To a solution of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]propanoate(250 mg, 566 umol) in THF (50 mL) was added Pd/C (50 mg, 10% purity) andPd(OH)₂/C (50 mg, 10% purity). The mixture was stirred at 25° C. for 5hrs under H₂ atmosphere (15 psi). On completion, the mixture wasfiltered and the filtrate was concentrated in vacuo to give the titlecompound (200 mg, 79% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 7.07-6.98 (m, 2H), 6.90-6.83 (m, 1H), 5.34 (dd, J=5.2,12.8 Hz, 1H), 3.63-3.53 (m, 2H), 3.39-3.37 (m, 2H), 3.33 (s, 3H),3.02-2.83 (m, 1H), 2.78-2.58 (m, 4H), 2.43 (t, J=6.0 Hz, 2H), 2.07-1.94(m, 1H), 1.85-1.74 (m, 2H), 1.41 (s, 9H).

Step4-3-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]propanoicAcid (7)

To a solution of tert-butyl3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]propanoate (150 mg, 336 umol) in DCM (4 mL) was added TFA (4.62 g, 40.0mmol, 3.00 mL). The mixture was stirred at 25° C. for 2 hrs. Oncompletion, the mixture was concentrated in vacuo to give the titlecompound (120 mg, 91% yield) as brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.08 (s, 1H), 7.11-6.95 (m, 2H), 6.87 (dd, J=1.2, 8.0 Hz, 1H), 5.34(dd, J=5.2, 12.8 Hz, 1H), 3.58 (t, J=6.4 Hz, 2H), 3.38 (t, J=6.4 Hz,2H), 3.33 (s, 3H), 2.99-2.84 (m, 1H), 2.76-2.57 (m, 4H), 2.46 (t, J=6.4Hz, 2H), 2.03-1.98 (m, 1H), 1.86-1.74 (m, 2H).

Step5-3-[3-Methyl-2-oxo-5-[3-[3-oxo-3-[4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]propoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-437)

A mixture of3-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]propanoicacid (120 mg, 308 umol),N-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-amine (129 mg, 308 umol, HCl, Intermediate OP), DIEA (119 mg,924 umol), HATU (140 mg, 369 umol) in DMF (3 mL) was degassed and purgedwith N₂ for 3 times, and then the mixture was stirred at 25° C. for 2hrs under N₂ atmosphere. On completion, the mixture was concentrated invacuo. The residue was purified by Pre-HPLC (column: Phenomenex SynergiC18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 11%-39%, 9min) to give the title compound (55.0 mg, 24% yield) as white solid. ¹HNMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.79 (s, 1H), 7.55 (d, J=2.8 Hz,1H), 7.08-6.97 (m, 2H), 6.87 (d, J=7.6 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H),6.21 (d, J=7.6 Hz, 1H), 5.34 (dd, J=5.2, 12.8 Hz, 1H), 4.10-4.01 (m,1H), 3.95-3.85 (m, 2H), 3.64-3.48 (m, 8H), 3.34-3.30 (m, 7H), 2.96-2.86(m, 1H), 2.70-2.54 (m, 7H), 2.48-2.42 (m, 2H), 2.38-2.28 (m, 1H),2.03-1.96 (m, 3H), 1.88-1.71 (m, 6H), 1.71-1.59 (m, 2H), 1.57-1.46 (m,2H), 1.43-1.27 (m, 2H), LC-MS (ESI⁺) m/z 756.5 (M+1)⁺.

Example 433:3-[3-Methyl-2-oxo-5-[7-oxo-7-[4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]heptyl]benzimidazol-1-yl]piperidine-2,6-dione(I-438)

Step1-7-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]hept-6-ynoicacid (3)

A mixture of hept-6-ynoic acid (224 mg, 1.77 mmol, CAS #30964-00-2),3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (200mg, 591 umol, Intermediate HN), Pd(PPh₃)₂Cl₂ (12.5 mg, 17.7 umol), CuI(1.13 mg, 5.91 umol) and DIEA (1.53 g, 11.8 mmol) in DMSO (5 mL) wasdegassed and purged with N₂ for 3 times in glove box. The mixture wasstirred at 80° C. for 2 hrs under N₂ atmosphere. On completion, thecrude product was purified by reverse phase column (0.1% FA condition)to give the title compound (180 mg, 60% yield) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ=11.12 (s, 1H), 7.97-7.67 (m, 1H), 7.29-7.18 (m,1H), 7.17-7.03 (m, 2H), 5.37 (d, J=13.2 Hz, 1H), 3.43-3.38 (m, 3H),2.93-2.81 (m, 2H), 2.74-2.65 (m, 1H), 2.46-2.39 (m, 2H), 2.30-2.23 (m,2H), 2.02 (d, J=4.4 Hz, 1H), 1.72-1.43 (m, 4H).

Step 2—Tert-Butyl6-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate(4)

To a solution of7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]hept-6-ynoicacid (160 mg, 417 umol) in THF (50 mL) was added Pd/C (200 mg, 417 umol,50% purity) and Pd(OH)₂/C (200 mg, 417 umol, 10% purity) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred at 15° C. for 2 hours under H₂ (15 psi). Oncompletion, the mixture was filtered with Clite and the filtrate wasconcentrated in vacuo to give the title compound (100 mg, 40% yield) asa yellow solid. LC-MS (ESI⁺) m/z 388.2 (M+H)⁺.

Step3-3-[3-Methyl-2-oxo-5-[7-oxo-7-[4-[4-[(5-tetrahydropyran-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-yl)amino]cyclohexyl]piperazin-1-yl]heptyl]benzimidazol-1-yl]piperidine-2,6-dione(I-438)

To a solution of7-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]heptanoicacid (100 mg, 258 umol) andN-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 258 umol, Intermediate OP) in DMF (5 mL) wasadded HATU (118 mg, 310 umol) and DIEA (83.4 mg, 645 umol, 112 uL). Themixture was stirred at 25° C. for 6 hrs. On completion, the residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.05% HCl)-ACN]; B %: 17%-35%, 9 min) to give thetitle compound (26.0 mg, 12.0% yield) as a light yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.16 (s, 1H), 11.10 (s, 1H), 7.97 (s, 1H), 7.80(s, 1H), 7.05-7.00 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.71 (d, J=2.4 Hz,1H), 5.35 (dd, J=5.6, 12.8 Hz, 1H), 4.49 (d, J=14.4 Hz, 1H), 4.06 (d,J=11.2 Hz, 2H), 3.92 (d, J=8.0 Hz, 4H), 3.50-3.48 (m, 3H), 3.33 (s, 3H),3.21-3.06 (m, 4H), 2.98-2.84 (m, 2H), 2.70-2.67 (m, 1H), 2.66-2.59 (m,4H), 2.40-2.34 (m, 2H), 2.25 (s, 2H), 2.09 (s, 2H), 2.04-1.97 (m, 1H),1.80-1.64 (m, 10H), 1.50 (s, 2H), 1.33-1.30 (m, 4H); LC-MS (ESI⁺) m/z754.5 (M+H)⁺.

Example 434:3-[3-Methyl-4-[3-[2-[2-[2-[2-[methyl-[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(I-439)

To a mixture ofN1-methyl-N4-(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine(80.0 mg, 242 umol, Intermediate OQ) in a mixed solvent of THF (6 mL)and DMF (1.5 mL) was added TEA (36.8 mg, 364 umol), HOAc (21.8 mg, 364umol) and2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetaldehyde(119 mg, 242 umol, from Example 437). The mixture was stirred for 30minutes, and then NaBH(OAc)₃ (102 mg, 485 umol) was added. The mixturewas stirred 25° C. for 48 hours. On completion, the reaction mixture wasquenched by water (15 mL), and then extracted with EA (3×30 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.05% HCl)-ACN]) to give the title compound (6.12 mg, 2% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 8.30 (s, 1H), 7.19 (s,1H), 6.96 (d, J 4.8 Hz, 2H), 6.91-6.83 (m, 1H), 5.30 (dd, J 5.6, 12.4Hz, 1H), 3.89-3.86 (m, 2H), 3.69-3.34 (m, 24H), 3.24-3.16 (m, 2H),2.98-2.79 (m, 3H), 2.74 (s, 3H), 2.70-2.57 (m, 2H), 2.15-1.94 (m, 5H),1.85-1.75 (m, 4H), 1.71-1.49 (m, 6H); LC-MS (ESI⁺) m/z 805.6 (M+H)⁺.

Example 435:2-[2-[2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]-N-[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]acetamide(I-440)

To a solution of2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetic acid (70.7 mg, 113 umol, from Example 447)and N4-(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine (40.0 mg, 113 umol, HCl, fromI-442) in DMF (5 mL) was HATU (51.9 mg, 136 umol) and DIPEA (73.5 mg,568 umol, 99.0 uL). The mixture was stirred at 25° C. for 1.5 hrs. Oncompletion, the mixture was quenched with H₂O (5 mL), then concentratedin vacuo to give a residue. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 7%-37%, 10 min) to give the title compound (33.2mg, 36% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.31 (s,1H), 11.10 (s, 1H), 8.06 (s, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.99-6.90 (m,2H), 6.90-6.81 (m, 2H), 5.57 (d, J=8.0 Hz, 1H), 5.35 (dd, J=5.2, 12.4Hz, 1H), 4.15-4.00 (m, 1H), 3.93-3.87 (m, 2H), 3.85 (s, 2H), 3.60-3.52(m, 17H), 3.47-3.44 (m, 2H), 3.28-3.19 (m, 2H), 2.96-2.91 (m, 2H),2.90-2.83 (m, 1H), 2.71-2.58 (m, 2H), 2.03-1.93 (m, 3H), 1.87-1.76 (m,6H), 1.59-1.36 (m, 6H); LC-MS (ESI⁺) m/z 805.5 (M+H)⁺.

Example 436:N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide(I-441)

Step 1—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-(4-methoxycarbonylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(3)

To a solution of methyl4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate (650 mg, 2.43 mmol,Intermediate FW),5-(4-tertbutoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (650 mg, 1.87 mmol) in ACN (15.0 mL) was added DIEA (725 mg, 5.61mmol), HATU (1.42 g, 3.74 mmol). The mixture was stirred at 60° C. for16 hrs. On completion, the mixture was concentrated in vacuo. Themixture was purified by reverse phase: (0.10% FA) to give the titlecompound (700 mg, 62% yield) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ9.60 (s, 1H), 9.05 (s, 1H), 8.48 (s, 1H), 8.38 (d, J=8.0 Hz, 1H), 8.17(d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 6.92 (t, J=54.0 Hz, 1H), 6.46(d, J=8.0 Hz, 1H), 3.96 (s, 3H), 3.91-3.80 (m, 4H), 3.70-3.60 (m, 4H),1.54 (s, 9H).

Step2-4-[4-[[5-(4-Tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicAcid (4)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-(4-methoxycarbonylphenyl) pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (1.00g, 1.68 mmol) in THF (40.0 mL) and H₂O (8 mL) was added LiOH (200 mg,8.38 mmol). The mixture was stirred at 20° C. for 16 hrs. On completion,the mixture was concentrated in vacuo. The mixture was diluted with H₂O(30 mL). The mixture was acidified with 1N HCl solution till pH=5,filtered and the filter cake was dried in vauco to give the titlecompound (900 mg, 92% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 12.01 (s, 1H), 9.48 (s, 1H), 9.08 (s, 1H), 8.82 (d, J=8.0 Hz, 1H),8.32 (s, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 7.35 (t,J=53.6 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 3.90-3.75 (m, 4H), 3.50-3.45 (m,4H), 1.44 (s, 9H).

Step 3—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-(4-isopropoxycarbonyloxycarbonylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(6)

To a solution of4-[4-[[5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoic acid (900 mg, 1.54 mmol),TEA (625 mg, 6.18 mmol) in THF (30.0 mL) was added isopropylcarbonochloridate (473 mg, 3.86 mmol) at −10° C. The mixture was stirredat −10° C. for 1 hr. On completion, the mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (1.00 g,90% yield) as yellow solid. LC-MS (ESI⁺) m/z 669.2 (M+H)⁺.

Step 4—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(7)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-(4-isopropoxycarbonyloxycarbonylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(1.00 g, 1.50 mmol) in THF (50.0 mL) and H₂O (10.0 mL) was added LiBH₄(195 mg, 8.97 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hr.On completion, the mixture was quenched with H₂O (10 mL), then extractedwith DCM (2×30 mL). The organic layers were dried with anhydrous Na₂SO₄,filtered and concentrated in vacuo. The mixture was triturate with DCM(5 mL) to give the title compound (700 mg, 82% yield) as yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.98 (s, 1H), 8.85 (d, J=8.0Hz, 1H), 8.33 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H),7.20 (t, J=53.2 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 5.35-5.24 (m, 1H), 4.56(d, J=4.4 Hz, 2H), 3.95-3.75 (m, 4H), 3.55-3.45 (m, 4H), 1.45 (s, 9H).

Step 5—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (8)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (700mg, 1.23 mmol) in THF (30.0 mL) was added DMP (626 mg, 1.48 mmol). Themixture was stirred at 20° C. for 1 hour. On completion, the mixture wasquenched with saturated Na₂S₂O₃ (30 mL) and washed with saturated NaHCO₃(2×30 mL). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo to give the title compound (680 mg, 90% yield)as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.52 (s,1H), 9.17 (s, 1H), 8.86 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.15-8.10 (m,2H), 8.09-8.03 (m, 2H), 7.39 (t, J=52.8 Hz, 1H), 6.96-6.86 (m, 1H),3.90-3.80 (m, 4H), 3.50-3.40 (m, 4H), 1.45 (s, 9H).

Step 6—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-[4-[[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(10)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (129 mg, 227umol), 3-[5-[4-(4-aminobutoxy)butyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (100 mg,227 umol, HCl, Intermediate OD) in THF (40.0 mL) was added TEA (46.1 mg,455 umol) and HOAc (41.0 mg, 683 umol). The mixture was stirred at 20°C. for 0.5 hr, then NaBH(OAc)₃ (144 mg, 683 umol) was added. The mixturewas stirred at 20° C. for 16 hrs. On completion, the mixture was dilutedwith H₂O (2 mL) and concentrated in vacuo. The mixture was purified byreverse phase column (0.1% FA) to give the title compound (60.0 mg, 27%yield) as yellow solid. LC-MS (ESI⁺) m/z 953.4 (M+H)⁺.

Step7—N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide(I-441)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-[4-[[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(60.0 mg, 62.9 umol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M,5.00 mL). The mixture was stirred at 20° C. for 0.5 hr. On completion,the mixture was concentrated in vacuo. The mixture was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 8%-32%, 8 min) to give the title compound(31.2 mg, 54% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.00(s, 1H), 9.51(s, 1H), 9.01 (s, 1H), 8.80 (d, J=8.0 Hz, 1H), 8.32 (s,1H), 8.28 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.29(t, J=53.6 Hz, 1H), 7.04-6.96 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 6.86 (d,J=8.0 Hz, 1H), 5.42-5.26 (m, 1H), 3.90-3.86 (m, 4H), 3.67-3.54 (m, 4H),3.40-3.33 (m, 4H), 3.31 (s, 3H), 2.88 (s, 4H), 2.75-2.70 (m, 1H),2.70-2.65 (m, 2H), 2.65-2.61 (m, 1H), 2.61-2.59 (m, 1H), 2.05-1.95 (m,1H), 1.66-1.48 (m, 8H); LC-MS (ESI⁺) m/z 853.3 (M+H)⁺.

Example 437:3-[3-Methyl-2-oxo-4-[3-[2-[2-[2-[2-[[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-442)

Step1-2-[(5-Bromo-4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(2)

NaH (2.1 g, 52.5 mmol, 60% purity) was suspended in dimethylformamide(50 mL). The mixture was stirred for 10 min and then cooled at 0° C.with an ice bath. 5-bromo-4-chloro-7H-pyrrolo[2,3-d] pyrimidine (10 g,43.0 mmol) dissolved in dimethylformamide (50 mL) was added drop-wiseand the mixture was stirred for 30 min. At the same temperature2-(chloromethoxy)ethyl-trimethyl-silane (9.00 g, 53.9 mmol, 9.55 mL)dissolved in dimethylformamide (50 mL) was added drop-wise and stirredfor 30 min at 0° C. On completed, the mixture was quenched with water(30 mL), extracted with ethyl acetate (3×30 mL). The combined organiclayers was washed with brine (2×10 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The reaction mixture waspurified by silica gel chromatography (PE:EA=30:1) to give the titlecompound (13.2 g, 85% yield) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ8.71-8.50 (m, 1H), 7.81 (s, 1H), 5.67 (s, 2H), 3.69-3.54 (m, 2H),0.94-0.83 (m, 3H), −0.06 (s, 9H), LC-MS (ESI⁺) m/z 361.9 (M+H)⁺.

Step 2—Tert-ButylN-[4-[[5-bromo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate(4)

To a solution of2-[(5-bromo-4-chloro-pyrrolo[2,3-d]pyrimidin-7-yl)methoxy]ethyl-trimethyl-silane(1 g, 2.76 mmol) and tert-butyl N-(4-aminocyclohexyl)carbamate (591 mg,2.76 mmol, CAS #177906-48-8) in ACN (20 mL) was added Na₂CO₃ (585 mg,5.52 mmol). The reaction mixture was stirred at 80° C. for 12 hrs. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The crude product was triturated with ethyl acetate (10 mL) to give thetitle compound (1.48 g, 95% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 8.33 (s, 1H), 7.06 (s, 1H), 5.91 (d, J=7.2 Hz, 1H), 5.52 (s,2H), 4.45 (s, 1H), 4.14 (d, J=7.2 Hz, 1H), 3.60-3.46 (m, 3H), 2.25 (d,J=9.8 Hz, 2H), 2.16-2.05 (m, 2H), 1.47 (s, 9H), 1.44-1.34 (m, 4H),0.98-0.86 (m, 2H), −0.03 (s, 9H). LC-MS (ESI⁺) m/z 540.1; 542.1 (M+H,M+3)⁺.

Step 3—Tert-ButylN-[4-[[5-(3,6-dihydro-2H-pyran-4-yl)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate (6)

A mixture of tert-butylN-[4-[[5-bromo-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate (1.34 g, 2.48 mmol),2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.56 g, 7.44 mmol, CAS #287944-16-5), Berttphos-Pd-G₃ (224 mg, 247umol, CAS #1470372-59-8) and K₂CO₃ (685 mg, 4.96 mmol) in a mixedsolvent of THF (20 mL) and H₂O (4 mL) was degassed and purged with N₂for 3 times, and then the mixture was stirred at 55° C. for 3 hrs underN₂ atmosphere. On completion, the reaction mixture was concentrated invacuo. The residue was washed with ethyl acetate (50 mL). After, theorganic layer was concentrated in vacuo. The crude product was purifiedby reversed-phase HPLC (0.1% FA condition) to give the title compound(1.06 g, 78% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28(s, 1H), 7.44 (s, 1H), 6.81 (d, J=7.6 Hz, 1H), 5.89 (s, 1H), 5.68 (d,J=7.6 Hz, 1H), 5.55 (s, 2H), 4.32 (d, J=2.0 Hz, 2H), 4.04 (s, 1H), 3.92(t, J=5.2 Hz, 2H), 3.58 (t, J=8.0 Hz, 2H), 3.37-3.30 (m, 1H), 2.52 (s,2H), 2.10 (d, J=8.0 Hz, 2H), 1.90 (s, 2H), 1.46 (s, 9H), 1.45-1.36 (m,4H), 0.90 (t, J=8.0 Hz, 2H), 0.00 (s, 9H); LC-MS (ESI⁺) m/z 544.4(M+H)⁺.

Step 4—Tert-ButylN-[4-[[5-tetrahydropyran-4-yl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate(7)

To a solution of tert-butylN-[4-[[5-(3,6-dihydro-2H-pyran-4-yl)-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate (1.06 g,1.95mmol) in methanol (5 mL) was added Pd/C (100 mg, 163 umol, 10%, wt)under N₂. The suspension was degassed under vacuum and purged with H₂several times. The mixture was stirred under H₂ (15 psi) at 20° C. for36 hrs. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo to give the title compound (1.00 g, 94% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (s, 1H), 7.12 (s, 1H),6.83 (d, J=7.6 Hz, 1H), 5.81 (d, J=7.6 Hz, 1H), 5.52 (s, 2H), 4.13 (d,J=7.6 Hz, 1H), 4.00 (dd, J=2.8, 11.2 Hz, 2H), 3.65 (t, J=11.2 Hz, 2H),3.56 (t, J=8.0 Hz, 2H), 3.38-3.32 (m, 1H), 2.04 (d, J=10.8 Hz, 2H),1.98-1.92 (m, 3H), 1.70-1.54 (m, 4H), 1.48 (s, 9H), 1.46-1.27 (m, 4H),0.91-0.83 (m, 2H), 0.00 (s, 9H); LC-MS (ESI⁺) m/z 546.4 (M+H)⁺.

Step5—[4-[(4-Aminocyclohexyl)amino]-5-tetrahydropyran-4-yl-pyrrolo[2,3-d]pyrimidin-7-yl]methanol(8)

To a solution of tert-butylN-[4-[[5-tetrahydropyran-4-yl-7-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-d]pyrimidin-4-yl]amino]cyclohexyl]carbamate (1.00 g, 1.83 mmol) inDCM (20 mL) was added HCl/dioxane (4 M, 30 mL). The reaction mixture wasstirred at 20° C. for 12 hrs. On completion, the reaction mixture wasconcentrated in vacuo to give the title compound (633 mg, 100% yield) asa white solid. LC-MS (ESI⁺) m/z 346.2 (M+H)⁺.

Step6—N4-(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine(9)

To a solution of[4-[(4-aminocyclohexyl)amino]-5-tetrahydropyran-4-yl-pyrrolo[2,3-d]pyrimidin-7-yl]methanol(633 mg, 1.83 mmol) in a mixed solvent of THF (3 mL), H₂O (1 mL) andMeOH (1 mL) was added LiOH·H₂O (384 mg, 9.16 mmol). The reaction mixturewas stirred at 20° C. for 12 hrs. On completion, the reaction mixturewas acidified with HCl (2 N) to pH=2. The reaction mixture wasconcentrated in vacuo. The crude product was purified by reversed-phaseHPLC (0.1% NH₃ H₂O condition) to give the title compound (250 mg, 43%yield) was added as a green solid. LC-MS (ESI⁺) m/z 316.2 (M+H)⁺.

Step 7-2-[2-[2-(2-Prop-2-ynoxyethoxy)ethoxy]ethoxy]ethanol (12)

To a mixture of 2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethanol (20.0 g,102 mmol, 17.7 mL) and 3-bromoprop-1-yne (14.7 g, 123 mmol) in THF (200mL) was added TBAI (2.28 g, 6.18 mmol), KI (2.56 g, 15.45 mmol) and KOH(5.78 g, 102 mmol). The mixture was stirred at 25° C. for 12 hours. Oncompletion, the reaction mixture was filtered and concentrated in vacuo.The residue was purified by column chromatography (PE:EA=5/1 to 0/1) togive the title compound (16.0 g, 67% yield) as a light yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 4.18 (d, J=2.4 Hz, 2H), 3.70 (d, J=4.8 Hz, 2H),3.67 (d, J=3.2 Hz, 2H), 3.69-3.61 (m, 10H), 3.60-3.57 (m, 2H), 2.73 (s,1H), 2.42 (t, J=2.4 Hz, 1H).

Step8-3-[4-[3-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(14)

To a mixture of 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]ethanol(1.03 g, 4.44 mmol) and3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (0.50g, 1.48 mmol, Intermediate HP) in DMSO (20 mL) was added CuI (56.3 mg,295 umol), P(t-Bu)₃ (2.30 g, 1.48 mmol, 2.67 mL, 13% purity, a solutionof toluene), DIEA (955 mg, 7.39 mmol) and Pd(PPh₃)₂Cl₂ (103 mg, 147umol). The reaction mixture was stirred at 80° C. for 3 hours. Oncompletion, the reaction mixture was diluted with water (60 mL) andextracted with EA (4×60 mL). The combined organic layers was dried overNa₂SO₄, filtered and concentrated in vacuo to give a residue. The crudeproduct was purified by prep-HPLC (0.1% FA condition) to give the titlecompound (0.50 g, 69% yield) as brown oil. ¹H NMR (400 MHz, DMSO-d₆)δ=11.11 (s, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.15-7.11 (m, 1H), 7.06-7.00(m, 1H), 5.40 (dd, J=5.2, 12.8 Hz, 1H), 4.55 (t, J=5.2 Hz, 1H), 4.46 (s,2H), 3.70-3.61 (m, 5H), 3.60-3.57 (m, 2H), 3.53-3.51 (m, 6H), 3.49-3.47(m, 4H), 3.41-3.39 (m, 2H), 2.95-2.84 (m, 1H), 2.77-2.58 (m, 2H),2.07-1.99 (m, 1H).

Step9-3-[4-[3-[2-[2-[2-(2-Hydroxyethoxy)ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(15)

To a mixture of3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(200 mg, 408 umol) in THF (10 mL) was added Pd/C (100 mg, 10% wt) andPd(OH)₂/C (100 mg, 10% wt). The reaction mixture was stirred at 25° C.for 12 hours under H₂ (15 Psi) atmosphere. On completion, the reactionmixture was concentrated in vacuo to give the title compound (180 mg,89% yield) as white solid which was used for the next step withoutpurification. ¹H NMR (400 MHz, DMSO-d₆) b 11.09 (s, 1H), 6.96 (d, J=4.4Hz, 2H), 6.90-6.86 (m, 1H), 5.36 (dd, J=5.2, 12.4 Hz, 1H), 4.57 (t,J=5.2 Hz, 1H), 4.03 (q, J=7.2 Hz, 1H), 3.56 (s, 3H), 3.52 (d, J=5.6 Hz,10H), 3.48-3.45 (m, 4H), 3.40 (d, J=5.2 Hz, 2H), 2.98-2.93 (m, 2H),2.89-2.84 (m, 1H), 2.72-2.63 (m, 2H), 2.61-2.58 (m, 2H), 2.02-1.96 (m,2H), 1.85-1.81 (m, 1H); LC-MS (ESI⁺) m/z 494.3 (M+H)⁺.

Step10-2-[2-[2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetaldehyde(16)

To a mixture of3-[4-[3-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(180 mg, 364 umol) in THF (20 mL) was added DMP (309 mg, 729 umol). Thereaction mixture was stirred at 25° C. for 1.5 hours. On completion, thereaction mixture was quenched by saturated Na₂S₂O₃ (15 mL) and saturatedNaHCO₃ (15 mL) at 25° C., and then stirred for 30 minutes, then theorganic layers were separated and concentrated in vacuo to give thetitle compound (179 mg, 100% yield) as a red oil. ¹H NMR (400 MHz,DMSO-d₆) δ 11.07 (s, 1H), 9.56 (s, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.88 (d,J=8.8 Hz, 1H), 5.41-5.31 (m, 1H), 4.16 (s, 2H), 3.60-3.43 (m, 15H),3.01-2.92 (m, 2H), 2.90-2.84 (m, 1H), 2.74-2.54 (m, 4H), 2.04-1.96 (m,1H), 1.85-1.81 (m, 2H). LC-MS (ESI⁺) m/z 492.3 (M+H)⁺.

Step11-3-[3-Methyl-2-oxo-4-[3-[2-[2-[2-[2-[[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-442)

To a solution ofN4-(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,4-diamine(50.0 mg, 158 umol) and2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetaldehyde(77.9 mg, 158 umol) in a mixed solvent of THF (5 mL) and DMF (1 mL) wasadded HOAc (9.52 mg, 158. umol) and NaBH(OAc)₃ (40.3 mg, 190 umol). Thereaction mixture was stirred at 20° C. for 12 hrs. On completion, thereaction mixture was concentrated in vacuo. The crude product waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 13%-31%, 6 min) to give thetitle compound (11.0 mg, 8% yield) as white solid. ¹H NMR (400 MHz,DMSO-d₆) b 11.35 (s, 2H), 8.35 (s, 1H), 8.08 (s, 1H), 7.05-6.80 (m, 4H),5.60 (d, J=7.6 Hz, 1H), 5.36 (dd, J=4.8, 12.0 Hz, 1H), 4.05 (s, 1H),3.90 (d, J=8.4 Hz, 2H), 3.59-3.49 (m, 20H), 3.45 (t, J=5.6 Hz, 2H),3.26-3.21 (m, 1H), 3.01-2.91 (m, 4H), 2.90-2.84 (m, 1H), 2.76-2.67 (m,1H), 2.62 (m, 1H), 2.13-1.78 (m, 9H), 1.60-1.34 (m, 6H). LC-MS (ESI⁺)m/z 791.5 (M+H)⁺.

Example 438:3-[3-Methyl-2-oxo-4-[3-[2-[2-[2-[2-oxo-2-[4-[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-444)

Step 1—Tert-Butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]acetate(3)

To a mixture of3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (600mg, 1.77 mmol, Intermediate HP), tert-butyl2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]acetate (1.07 g, 3.55 mmol,from Example 441) in DMF (10 mL) was added CuI (67.6 mg, 355 umol),Cs₂CO₃ (2.89 g, 8.87 mmol) and Pd(PPh₃)₂Cl₂ (249 mg, 355 umol) under N₂.The reaction mixture was stirred at 80° C. for 3 hours. On completion,the mixture was poured into water (30 mL). The aqueous phase wasextracted with ethyl acetate (2×30 mL). The combined organic phase waswashed with brine (2×30 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byreversed-phase (0.1% FA condition) to give the title compound (598 mg,60% yield) as brown oil. ¹H NMR (400 MHz, CDCl₃) δ 8.29 (s, 1H), 7.16(d, J 7.6 Hz, 1H), 6.97 (t, J 8.0 Hz, 1H), 6.75 (d, J 8.0 Hz, 1H),5.23-5.15 (m, 1H), 4.46 (s, 2H), 4.01 (s, 2H), 3.76 (s, 3H), 3.76-3.66(m, 12H), 2.99-2.68 (m, 3H), 2.29-2.16 (m, 1H), 1.46 (s, 9H).

Step 2—Tert-Butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetate(4)

To a solution of tert-butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]acetate(578 mg, 1.03 mmol) in THF (5 mL) was added Pd/C (100 mg, 20% purity)and Pd(OH)₂/C (100 mg, 20% purity) under N₂. The suspension was degassedunder vacuum and purged with H₂ 3 times. The mixture was stirred at 20°C. for 12 hours under H₂ (15 psi). On completion, the mixture wasconcentrated in vacuo to give a title compound (540 mg, 92% yield) asbrown oil. LC-MS (ESI⁺) m/z 586.3 (M+Na)⁺.

Step3-2-[2-[2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]aceticAcid (5)

To a mixture of tert-butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetate(520 mg, 922 umol) in DCM (2 mL) was added TFA (210 mg, 1.85 mmol). Thereaction mixture was stirred at 20° C. for 1 hour. On completion, themixture was concentrated in vacuo to give a residue. The residue waspurified by column chromatography to give the title compound (436 mg,93% yield) as brown oil. LC-MS (ESI⁺) m/z 508.3 (M+H)⁺.

Step4-3-[3-Methyl-2-oxo-4-[3-[2-[2-[2-[2-oxo-2-[4-[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-444)

To a mixture of2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethoxy]ethoxy]acetic acid (39.6 mg, 78.0 umol),N-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (30.0 mg, 78.0 umol,Intermediate OP) in DMF (1.5 mL) was added DIEA (30.2 mg, 234 umol) andHATU (35.6 mg, 93.6 umol). The reaction mixture was stirred at 20° C.for 1 hr. On completion, water (1.5 mL) was added into the reactionmixture and the mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 7%-27%) togive the title compound (2.00 mg, 2% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.08 (s, 1H), 9.07 (s, 11H), 8.10 (s, 1H),7.07-6.80 (m, 4H), 5.36 (d, J=5.2, 12.4 Hz, 1H), 4.18 (s, 2H), 3.90 (d,J=10.4 Hz, 2H), 3.66-3.50 (m, 22H), 3.48-3.40 (m, 6H), 3.17-3.06 (m,4H), 3.00-2.83 (m, 5H), 2.75-2.56 (m, 3H), 2.25-1.94 (m, 4H), 1.84 (d,J=8.0 Hz, 4H), 1.60-1.46 (m, 4H); LC-MS (ESI⁺) m/z 874.5 (M+H)⁺.

Example 439:N-[3-(difluoromethyl)-1-[4-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylcarbamoyl]phenyl]pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide(I-445)

Step 1—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-[4-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(3)

To a solution of4-[4-[[5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoic acid (66.3 mg, 113 umol,from Example 436),3-[5-[4-(4-aminobutoxy)butyl]-3-methyl-2-oxobenzimidazol-1-yl]piperidine-2,6-dione(50.0 mg, 113 umol, HCl, Intermediate OD) in DMF (3.00 mL) was addedHATU (51.9 mg, 136 umol) and DIEA (73.6 mg, 569 umol). The mixture wasstirred at 20° C. for 0.5 hr. On completion, the mixture was dilutedwith H₂O (15 mL), filtered and the filter cake was concentrated in vacuoto give the title compound (90.0 mg, 81% yield) as yellow solid. LC-MS(ESI⁺) m/z 967.4 (M+H)⁺.

Step2—N-[3-(difluoromethyl)-1-[4-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylcarbamoyl]phenyl]pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide(I-445)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-[4-[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(150 mg, 155 umol) in DCM (5.00 mL) was added HCl/dioxane (4 M, 7.50mL). The mixture was stirred at 20° C. for 0.5 hr. On completion, themixture was concentrated in vacuo. The mixture was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 17%-41%, 8 min) to give the title compound (67.5mg, 49% yield) as off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s,1H), 9.53 (s, 1H), 9.10 (s, 1H), 8.79 (d, J=8.0 Hz, 1H), 8.56 (t, J=5.6Hz, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.04-7.98 (m, 2H), 7.97-7.92 (m,2H), 7.31 (t, J=5.6 Hz, 1H), 7.02 (s, 1H), 7.00 (d, J=8.0 Hz, 1H), 6.91(d, J=8.0 Hz, 1H), 6.88-6.83 (m, 1H), 5.37-5.28 (m, 1H), 3.77-3.70 (m,4H), 3.33-3.29 (m, 9H), 2.93-2.88 (m, 1H), 2.86-2.83 (m, 4H), 2.75-2.68(m, 1H), 2.65-2.62 (m, 2H), 2.61-2.57 (m, 1H), 2.06-1.97 (m, 1H),1.64-1.52 (m, 8H); LC-MS (ESI⁺) m/z 867.3 (M+H)⁺.

Example 440:N-[3-(difluoromethyl)-1-[4-[[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide(I-446)

Step 1—Tert-Butyl4-[3-[[3-(difluoromethyl)-1-[4-[[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(3)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate (128 mg, 226umol, from Example 436),3-[4-[3-[2-(2-aminoethoxy)ethoxy]propyl]-3-methyl-2-oxobenzimidazol-1-yl]piperidine-2,6-dione(100 mg, 226 umol, HCl, from Intermediate IQ) in THF (20.0 mL) was addedTEA (45.9 mg, 453 umol) and HOAc (40.8 mg, 680 umol). The mixture wasstirred at 20° C. for 0.5 hr, then NaBH(OAc)₃ (144 mg, 680 umol) wasadded. The mixture was stirred at 20° C. for 16 hrs. On completion, themixture was diluted with H₂O (2.00 mL). The mixture was concentrated invacuo. The mixture was purified by reverse phase column (0.1% FA) togive the title compound (180 mg, 83% yield) as yellow solid. LC-MS(ESI⁺) m/z 955.3 (M+H)⁺.

Step2—N-[3-(difluoromethyl)-1-[4-[[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-5-piperazin-1-1-pyrazolo[1,5-a]pyrimidine-3-carboxamide(I-446)

To a solution of tert-butyl4-[3-[[3-(difluoromethyl)-1-[4-[[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]pyrazolo[1,5-a]pyrimidin-5-yl]piperazine-1-carboxylate(180 mg, 188 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 6 mL). Themixture was stirred at 20° C. for 0.5 hr. On completion, the mixture wasconcentrated in vacuo. The mixture was purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 12%-33%, 7 min) to give the title compound (89.5 mg, 53%yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (s, 1H), 9.50(s, 1H), 9.50 (s, 1H), 8.98 (s, 1H), 8.82 (d, J=8.0 Hz, 1H), 8.33 (s,1H), 8.23 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.29(t, J=54 Hz, 1H), 6.95 (d, J=6.4 Hz, 2H), 6.92 (s, 1H), 6.88-6.83 (m,1H), 5.43-5.29 (m, 1H), 3.89 (s, 3H), 3.84 (s, 4H), 3.59-3.54 (m, 8H),3.49-3.44 (m, 2H), 2.94 (s, 4H), 2.94-2.91 (m, 2H), 2.91-2.85 (m, 1H),2.83-2.77 (m, 2H), 2.76-2.66 (m, 1H), 2.66-2.58 (m, 1H), 2.04-1.94 (m,1H), 1.89-1.76 (m, 2H); LC-MS (ESI⁺) m/z 855.5 (M+H)⁺.

Example 441:3-[3-Methyl-2-oxo-5-[3-[2-[2-[2-[2-oxo-2-[4-[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-447)

Step 1-2-[2-(2-Prop-2-ynoxyethoxy)ethoxy]ethanol (3)

To a solution of 2-[2-(2-hydroxyethoxy)ethoxy]ethanol (10.0 g, 66.5mmol, 8.93 mL, CAS #112-27-6) and 3-bromoprop-1-yne (7.92 g, 66.5 mmol,5.74 mL, CAS #106-96-7) in THF (100 mL) was added KI (1.66 g, 9.99mmol), TBAI (1.48 g, 4.00 mmol) and KOH (3.74 g, 66.5 mmol). Thereaction mixture was stirred at 25° C. for 16 hrs. On completion, themixture was filtered, and the filtrate was concentrated in vacuo to givea residue, the residue was diluted with H₂O (50 mL), and then extractedwith EA (2×80 mL), the organic phase was concentrated in vacuo to give aresidue. The residue was purified by column chromatography to give thetitle compound (10.0 g, 79% yield) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 4.19-4.12 (m, 2H), 3.74-3.57 (m, 10H), 3.57-3.52 (m, 2H), 2.42(s, 1H), 2.38 (t, J=2.4 Hz, 1H).

Step 2—Tert-Butyl 2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]acetate(5)

To a solution of 2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethanol (4.0 g, 21.25mmol) in THF (50 mL) was added NaH (1.28 g, 31.8 mmol, 60% purity) at 0°C., the mixture was stirred at 25° C. for 30 min, then tert-butyl2-chloroacetate (6.40 g, 42.5 mmol, 6.10 mL, CAS #107-59-5) was added tothe mixture, the reaction mixture was stirred at 25° C. for 12 hrs. Oncompletion, the mixture was quenched by H₂O (50 mL), and extracted withEA (2×100 mL). The organic phase was concentrated in vacuo to give aresidue. The residue was purified by column chromatography to give thetitle compound (3.60 g, 56% yield) as yellow oil. ¹H NMR (400 MHz,CDCl₃) δ 4.20 (d, J=2.4 Hz, 2H), 4.01 (s, 2H), 3.72-3.65 (m, 12H), 2.42(t, J=2.4 Hz, 1H), 1.47 (s, 9H).

Step 3—Tert-Butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]acetate(6)

To a solution of tert-butyl2-[2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethoxy]acetate (1.16 g, 3.84 mmol)and 3-(5-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione(650 mg, 1.92 mmol, Intermediate HN) in DMF (10 mL) was added CuI (73.2mg, 384 umol), Pd(PPh₃)₂Cl₂ (269 mg, 384 umol) and Cs₂CO₃ (3.13 g, 9.61mmol). The reaction mixture was stirred at 80° C. for 2 hrs under N₂. Oncompletion, the mixture was filtered and the filtrate was concentratedin vacuo to give a residue. The residue was purified by reverse phase(0.1% FA condition) to give the title compound (550 mg, 51% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.33 (s, 1H),7.21-7.09 (m, 2H), 5.39 (dd, J=5.2, 12.8 Hz, 1H), 4.39 (s, 2H), 3.97 (s,2H), 3.68-3.61 (m, 2H), 3.59-3.52 (m, 10H), 3.34 (s, 3H), 2.97-2.82 (m,1H), 2.76-2.57 (m, 2H), 2.06-2.00 (m, 1H), 1.41 (s, 9H); LC-MS (ESI⁺)m/z 582.3 (M+Na)⁺.

Step 4—Tert-Butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethoxy]acetate(7)

To a solution of tert-butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynoxy]ethoxy]ethoxy]ethoxy]acetate(550 mg, 982 umol) in THF (20 mL) was added Pd(OH)₂/C (250 mg, 915 umol,10% purity) and Pd/C (250 mg, 915 umol, 10% purity), the reactionmixture was stirred at 25° C. for 12 hrs under H₂ (15 Psi). Oncompletion, the residue was filtered and the filtrate was concentratedin vacuo to give the title compound (500 mg, 90% yield) as a whitesolid. LC-MS (ESI⁺) m/z 508.2 (M+H−56)⁺.

Step5-2-[2-[2-[2-[3-[1-(2,6-Dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethoxy]aceticAcid

To a solution of tert-butyl2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethoxy]acetate (100 mg, 177 umol) in DCM (3 mL)was added TFA (1.54 g, 13.5 mmol, 1 mL), the reaction mixture wasstirred at 25° C. for 12 hrs. On completion, the mixture wasconcentrated in vacuo to give the title compound (110 mg, 95% yield) ascolorless oil. LC-MS (ESI⁺) m/z 508.3 (M+H)⁺.

Step6-3-[3-Methyl-2-oxo-5-[3-[2-[2-[2-[2-oxo-2-[4-[4-[(5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl]piperazin-1-yl]ethoxy]ethoxy]ethoxy]ethoxy]propyl]benzimidazol-1-yl]piperidine-2,6-dione(I-447)

To a solution of2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethoxy]ethoxy]acetic acid (15.0 mg, 24.1 umol) andN-(4-piperazin-1-ylcyclohexyl)-5-tetrahydropyran-4-yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine(9.28 mg, 24.1 umol, Intermediate OP) in DMF (5 mL) was DIPEA (15.5 mg,120 umol, 21.0 uL) and HATU (11.0 mg, 28.9 umol). The mixture wasstirred at 25° C. for 1.5 hrs. On completion, the mixture was quenchedwith H₂O (5 mL), then concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 8%-32%, 8 min)to give the title compound (6.09 mg, 28% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 11.07 (s, 1H), 8.06 (s, 1H),7.05-6.96 (m, 2H), 6.92-6.78 (m, 2H), 5.51 (d, J=8.0 Hz, 1H), 5.32 (dd,J=5.2, 12.8 Hz, 1H), 4.12 (s, 2H), 4.08-3.98 (m, 1H), 3.94-3.85 (m, 2H),3.61-3.45 (m, 18H), 3.31 (s, 3H), 3.29-3.18 (m, 3H), 2.92-2.84 (m, 1H),2.71-2.57 (m, 4H), 2.49-2.39 (m, 4H), 2.36-2.28 (m, 1H), 2.07-1.94 (m,3H), 1.89-1.69 (m, 6H), 1.63-1.28 (m, 6H); LC-MS (ESI⁺) m/z 874.5(M+H)⁺.

TABLE 23 Compounds synthesized via Method 12 with the coupling ofvarious amines and acids in Step 1. LCMS Step 1 Step 1 (ES+)Intermediate Intermediate m/z Ex-#^(a) I-# Amine Acid (M + H)⁺ ¹HNMR(400 MHz, DMSO-d₆) δ 443 I-448 UD OM 928.6 11.05 (s, 1H), 10.98 (s, 1H),8.99 (s, 1H), 8.95 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.05-7.98 (m, 3H),7.74 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.18- 7.10 (m, 2H), 7.02-6.95(m, 3H), 6.83 (d, J = 8.0 Hz, 1H), 5.35-5.27 (m, 1H), 4.65-4.55 (m, 1H),4.36 (s, 1H), 3.52-3.45 (m, 8H), 3.29 (s, 3H), 3.21-3.17 (m, 2H),2.91-2.80 (m, 2H), 2.68-2.61 (m, 5H), 2.03- 1.94 (m, 1H), 1.85-1.74 (m,2H), 0.50-0.42 (m, 2H), 0.27-0.20 (m, 2H) 444 I-449 UE KR 929.1 11.09(s, 1H), 10.82 (s, 1H), 9.02 (s, 1H), 8.44-8.38 (m, 2H), 8.25-8.23 (m,2H), 7.56(dd, J = 7.2 Hz, J = 8.4 Hz, 1H), 7.41 (s, 1H), 7.25 (d, J =5.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.01 (d, J = 6.8 Hz, 1H), 6.58(bs, 1H), 5.06-5.03 (m, 1H), 4.37- 4.36 (m, 2H), 3.93-3.91 (m, 6H),3.53-3.44 (m, 22H), 2.88 (m, 1H), 2.60-2.54 (m, 2H), 2.03-2.01 (m, 1H)450 I-455 UX KR 885.4 11.07 (s, 1H), 10.81 (s, 1H), 8.97 (s, 1H), 8.46(s, 1H), 8.38 (s, 1H), 8.26- 8.21 (m, 2H), 7.69 (t, J = 5.6 Hz, 1H),7.25 (s, 1H), 7.16 (d, J = 5.2 Hz, 1H), 6.94 (d, J = 5.6 Hz, 1H), 6.84(d, J = 8.8 Hz, 1H), 5.41-5.30 (m, 1H), 4.27-4.21 (m, 2H), 3.93 (s, 3H),3.55-3.41 (m, 21H), 2.98- 2.82 (m, 3H), 2.63 (s, 1H), 2.60- 2.57 (m,1H), 2.02-1.95 (m, 1H), 1.85-1.74 (m, 2H) 451 I-456 VA KR 855.4 11.08(s, 1H), 11.03 (s, 1H), 8.96 (s, 1H), 8.41 (s, 1H), 8.25 (d, J = 5.2 Hz,1H), 7.70-7.62 (m, 1H), 7.58- 7.53 (m, 1H), 7.24 (s, 1H), 7.16 (d, J =4.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 6.8 Hz, 1H), 6.61-6.53 (m, 1H), 5.10-5.00 (m, 1H), 4.27-4.20 (m, 2H), 3.93 (s, 3H),3.69-3.41 (m, 16H), 3.28 (s, 3H), 2.93-2.82 (m, 1H), 2.63-2.57 (m, 1H),2.57-2.55 (m, 1H), 2.07-1.97 (m, 1H) 452 I-457 VK KR 968.4 11.09 (s,1H), 10.85 (s, 1H), 8.97 (s, 1H), 8.38 (s, 1H), 8.26-8.18 (m, 2H), 7.68(t, J = 6.4 Hz, 1H), 7.25 (s, 1H), 7.17 (d, J = 5.2 Hz, 1H), 7.00- 6.92(m, 2H), 6.90-6.83 (m, 1H), 5.36 (dd, J = 5.2, 12.8 Hz, 1H), 4.31- 4.19(m, 2H), 3.93 (s, 3H), 3.89- 3.82 (m, 1H), 3.57-3.50 (m, 19H), 2.98-2.86(m, 5H), 2.73-2.59 (m, 2H), 2.50-2.46 (m, 2H), 2.11-1.95 (m, 3H),1.88-1.78 (m, 2H), 1.73- 1.64 (m, 4H) 453 I-458 VO FX 924.5 10.97 (s,1H), 10.03 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.65 (s, 1H), 8.41 (s,1H), 8.16 (d, J = 5.6 Hz, 1H), 8.03-7.97 (m, 4H), 7.66 (d, J = 7.6 Hz,1H), 7.44 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.33-7.10 (m, 2H),7.07-7.04 (m, 1H), 6.57 (s, 1H), 6.04 (s, 1H), 5.15-5.06 (m, 1H),4.42-4.29 (m, 4H), 3.57-3.55 (m, 4H), 3.47-3.40 (m, 8H), 3.21-3.18 (m,2H), 2.96-2.85 (m, 1H), 2.64- 2.55 (m, 1H), 2.42-2.38 (m, 1H), 2.01-1.97(m, 1H), 1.12-1.05 (m, 1H), 0.49-0.44 (m, 2H), 0.25-0.22 (m, 2H) 454I-459 LG FX 851.1 11.07 (s, 1H), 10.02 (s, 1H), 8.98 (s, 1H), 8.92 (s,1H), 8.57 (t, J = 5.2 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.03- 7.96 (m,4H), 7.32 (t, J = 53.6 Hz, 1H), 7.12 (s, 1H), 7.08 (t, J = 5.6 Hz, 1H),7.06-7.02 (m, 2H), 7.01-6.97 (m, 1H), 6.90-6.85 (m, 1H), 5.33 (dd, J =5.6, 12.8 Hz, 1H), 3.45 (t, J = 6.0 Hz, 2H), 3.41-3.35 (m, 4H),3.31-3.31 (m, 3H), 3.19 (t, J = 6.0 Hz, 2H), 2.94-2.84 (m, 1H), 2.71-2.57 (m, 4H), 2.03-1.96 (m, 1H), 1.87-1.76 (m, 4H), 1.12-1.02 (m, 1H),0.49-0.43 (m, 2H), 0.26-0.19 (m, 2H) 455 I-460 LF FX 851.5 10.84 (s,1H), 9.79 (s, 1H), 8.74 (s, 1H), 8.68 (s, 1H), 8.34 (d, J = 5.6 Hz, 1H),7.93 (d, J = 5.2 Hz, 1H), 7.83-7.64 (m, 4H), 7.26-6.94 (m, 1H), 6.89 (s,1H), 6.87-6.80 (m, 2H), 6.75-6.70 (m, 2H), 6.65-6.61 (m, 1H), 5.15-5.10(m, 1H), 3.34 (s, 3H), 3.23 (d, J = 6.4 Hz, 6H), 2.95 (d, J = 6.4 Hz,2H), 2.77-2.70 (m, 2H), 2.47-2.39 (m, 2H), 2.11-2.07 (m, 1H), 1.80-1.72(m, 1H), 1.65- 1.54 (m, 4H), 0.87-0.80 (m, 1H), 0.25-0.19 (m, 2H),0.02-0.04 (m, 2H) 456 I-461 VR VQ 882.4 11.06 (s, 1H), 10.07 (s, 1H),9.14 (d, J = 2.4 Hz, 1H), 9.02 (s, 1H), 8.98 (s, 1H), 8.80-8.69 (m, 1H),8.45 (dd, J = 8.8 Hz, 1H), 8.20-8.13 (m, 2H), 7.49-7.19 (m, 1H), 7.12(s, 1H), 7.08 (t, J = 5.60 Hz, 1H), 7.04 (dd, J = 5.6, 1.6 Hz, 1H), 7.00(s, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 5.36-5.27(m, 1H), 3.62- 3.56 (m, 4H), 3.54-3.49 (m, 4H), 3.42-3.39 (m, 2H), 3.26(s, 3H), 3.19 (d, J = 6.4 Hz, 2H), 2.91-2.84 (m, 1H), 2.64-2.61 (m, 2H),2.03- 1.96 (m, 1H), 1.85-1.74 (m, 2H), 1.24 (d, J = 0.8 Hz, 1H),1.11-1.04 (m, 1H), 0.50-0.41 (m, 2H), 0.27- 0.17 (m, 2H) 457 I-462 PA FX868.4 11.20 (s, 1H), 10.05 (s, 1H), 8.98 (s, 1H), 8.91 (s, 1H), 8.66 (t,J = 5.6 Hz, 1H), 8.17 (d, J = 5.6 Hz, 1H), 8.04- 8.01 (m, 2H), 7.99-7.96(m, 2H), 7.45-7.18 (m, 2H), 7.16-7.12 (m, 2H), 7.11-7.07 (m, 1H), 7.05(d, J = 6.4 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 5.34 (dd, J = 5.2, 13.2Hz, 1H), 3.57 (d, J = 5.6 Hz, 8H), 3.53-3.51 (m, 2H), 3.19 (t, J = 5.6Hz, 2H), 2.88-2.85 (m, 1H), 2.75-2.58 (m, 4H), 2.15-2.14 (m, 1H),1.81-1.74 (m, 2H), 1.09-1.06 (m, 1H), 0.49- 0.44 (m, 2H), 0.26-0.22 (m,2H) 458 I-463 VT KR 841.4 11.08 (s, 1H), 10.82 (s, 1H), 8.97 (s, 1H),8.37 (s, 1H), 8.29-8.21 (m, 2H), 7.69 (t, J = 6.4 Hz, 1H), 7.25 (s, 1H),7.16 (d, J = 5.6 Hz, 1H), 7.04- 6.94 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H),5.32 (dd, J = 5.2, 12.8 Hz, 1H), 4.31-4.17 (m, 2H), 3.92 (s, 3H),3.57-3.50 (m, 8H), 3.48-3.40 (m, 4H), 3.30 (s, 3H), 3.25 (s, 2H), 2.95-2.83 (m, 1H), 2.75-2.60 (m, 4H), 2.02-1.97 (m, 1H), 1.85-1.72 (m, 2H)459 I-464 VU KR 841.3 11.08 (s, 1H), 10.82 (s, 1H), 8.97 (s, 1H), 8.37(s, 1H), 8.28-8.23 (m, 2H), 7.70 (t, J = 6.4 Hz, 1H), 7.25 (s, 1H), 7.16(d, J = 5.2 Hz, 1H), 6.97- 6.89 (m, 2H), 6.83 (dd, J = 2.8, 5.9 Hz, 1H),5.35 (dd, J = 5.2, 12.4 Hz, 1H), 4.30-4.19 (m, 2H), 3.91 (s, 3H),3.57-3.40 (m, 17H), 2.91 (t, J = 7.6 Hz, 2H), 2.88-2.83 (m, 1H),2.75-2.57 (m, 2H), 2.04-1.93 (m, 1H), 1.84-1.75 (m, 2H)  460^(b) I-465RD RX 866.4 11.07 (d, J = 4.4 Hz, 1H), 9.39 (s, 1H), 8.82 (d, J = 8.0Hz, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.29-6.98 (m, 1H), 6.97-6.84 (m,4H), 5.36 (d, J = 5.6, 12.8 Hz, 1H), 4.22 (s, 2H), 3.88 (s, 3H), 3.85(s, 3H), 3.66-3.45 (m, 22H), 2.96-2.84 (m, 3H), 2.73- 2.58 (m, 2H),2.04-1.95 (m, 1H), 1.85-1.74 (m, 2H)  461^(b) I-466 RD 2-[2-[2-[2-[3-866.1 11.07 (s, 1H), 9.38 (s, 1H), 8.79 (d, J = [1-(2,6-dioxo- 8.0 Hz,1H), 8.35 (s, 1H), 8.29 (s, 3-piperidyl)-3- 1H), 7.26-6.95 (m, 3H), 6.88(d, J = methyl-2-oxo- 8.0 Hz, 1H), 6.85-6.80 (m, 1H), benzimidazol- 5.32(dd, J = 5.2, 12.8 Hz, 1H), 4.21 5-yl]propoxy]- (s, 2H), 3.87 (s, 3H),3.84-3.81 (m, ethoxy]ethoxy]- 2H), 3.63-3.55 (m, 8H), 3.53-3.48ethoxy]acetic (m, 6H), 3.46-3.40 (m, 4H), 3.34- acid 3.32 (m, 2H), 3.30(s, 3H), 2.96- (synthesized 2.82 (m, 1H), 2.74-2.57 (m, 4H), via Steps1-5 2.05-1.95 (m, 1H), 1.82-1.70 (m, 2H) of Example 441, I-447)  462^(b)I-467 RD 2-[2-[2-[2-[2- 866.4 11.08 (s, 1H), 9.39 (s, 1H), 8.82 (d,[[2-(2,6-dioxo- J = 7.6 Hz, 1H), 8.42-8.26 (m, 2H), 3-piperidyl)-7.65-7.50 (m, 1H), 7.21-6.85 (m, 1,3-dioxo- 4H), 6.58 (d, J = 5.2 Hz,1H), 5.05 isoindolin-4- (d, J = 5.2, 12.8 Hz, 1H), 4.22 (s,yl]amino]ethoxy]- 2H), 3.94-3.81 (m, 7H), 3.64-3.51 ethoxy]ethoxy]- (m,18H), 3.44 (d, J = 5.6 Hz, 2H), ethoxy]acetic 2.99-2.77 (m, 1H), 2.61(d, J = 2.4 acid Hz, 2H), 2.14-1.92 (m, 1H) (synthesized via Steps 1-2of Example 161, I-161)  463^(b) I-468 RD 2-[2-[2-[2-[[2- 822.2 11.08 (s,1H), 9.37 (s, 1H), 8.80 (d, J = (2,6-dioxo-3- 8.0 Hz, 1H), 8.36 (s, 1H),8.29 (s, piperidyl)-1,3- 1H), 7.53 (d, J = 7.2, 8.4 Hz, 1H), dioxo-7.15-6.96 (m, 3H), 6.89 (d, J = 8.0 isoindolin-4- Hz, 1H), 6.57 (t, J =5.6 Hz, 1H), yl]amino]- 5.05 (d, J = 5.6, 12.8 Hz, 1H), 4.21ethoxy]ethoxy]- (s, 2H), 3.89 (s, 3H), 3.84 (s, 2H), ethoxy]acetic3.63-3.55 (m, 14H), 3.44 (d, J = 5.6 acid Hz, 2H), 3.29 (s, 2H),2.93-2.82 (m, (synthesized 1H), 2.62-2.53 (m, 2H), 2.06-1.98 (m, 1H) viaSteps 1-2 of Example 152, I-152)  464^(b) I-469 RD VW 778.3 11.07 (s,1H), 9.37 (s, 1H), 8.77 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 8.28 (s, 1H),7.27-6.90 (m, 3H), 6.87-6.81 (m, 2H), 5.33-5.29 (m, 1H), 4.24 (s, 2H),3.96-3.75 (m, 7H), 3.61 (m, 6H), 3.54-3.53 (m, 2H), 3.44-3.39 (m, 2H),3.29 (s, 3H), 2.95-2.84 (m, 1H), 2.74-2.57 (m, 4H), 2.04-1.96 (m, 1 H),1.84-1.73 (m, 2H) 465 I-470 VR VY 899.3 11.08 (s, 1H), 10.07 (s, 1H),8.98 (s, 1H), 8.95 (s, 1H), 8.43-8.33 (m, 1H), 8.15 (d, J = 5.4 Hz, 1H),7.91- 7.74 (m, 3H), 7.50-7.12 (m, 1H), 7.12-7.07 (m, 2H), 7.05-6.96 (m,3H), 6.90-6.82 (m, 1H), 5.32 (dd, J = 5.2, 12.8 Hz, 1H), 3.59-3.40 (m,10H), 3.30 (s, 3H), 3.18 (t, J = 6.0 Hz, 2H), 2.97-2.81 (m, 1H), 2.76-2.68 (m, 1H), 2.66-2.61 (m, 2H), 2.58-2.52 (m, 1H), 2.05-1.94 (m, 1H),1.85-1.74 (m, 2H), 1.15-0.98 (m, 1H), 0.49-0.41 (m, 2H), 0.26- 0.18 (m,2H) 466 I-471 4-[2-[2-[2-(2- WB 801.1 10.5 (s, 1H), 8.71 (d, J = 8.0 Hz,aminoethoxy)- 1H), 8.38 (s, 1H), 8.28-8.20 (m, ethoxy]ethoxy]- 2H), 8.05(t, J = 5.6 Hz, 1H), 7.54 ethylamino]- (dd, J = 7.2, 8.4 Hz, 1H), 7.08(d, J = 2-(2,6-dioxo- 8.8 Hz, 1H), 7.01 (d, J = 7.2 Hz, 3-piperidyl)1H), 6.83 (d, J = 8.0 Hz, 1H), 6.57 isoindoline- (t, J = 5.6 Hz, 1H),5.04 (dd, J = 5.6, 1,3-dione 12.8 Hz, 1H), 4.05-3.85 (m, 7H),(synthesized 3.61-3.57 (m, 2H), 3.55-3.50 (m, via Steps 1-2) 10H),3.45-3.38 (m, 4H), 2.93- 2.88 (m, 4H), 2.87-2.80 (m, 1H), 2.62-2.52 (m,2H), 2.06-1.98 (m, 1H) 467 I-472 HQ WD 874.4 11.07 (s, 1H), 9.98 (s,1H), 8.97 (d, J = 1.6 Hz, 1H), 8.92 (d, J = 1.6 Hz, 1H), 8.88 (s, 1H),8.81 (t, J = 5.2 Hz, 1H), 8.49 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 8.02(s, 1H), 7.55 (t, J = 6.4 Hz, 1H), 7.29-7.16 (m, 2H), 6.98- 6.88 (m,2H), 6.84-6.82 (m, 1H), 5.36-5.32 (m, 1H), 4.29-4.17 (m, 2H), 3.93 (s,3H), 3.57-3.44 (m, 13 H), 2.95-2.85 (m, 3H), 2.71-2.56 (m, 2 H),2.03-1.92 (m, 1 H), 1.84- 1.71 (m, 2H) 468 I-473 PP FX 865.8 11.09 (s,1H), 10.11-9.93 (m, 1H), 8.97 (s, 1H), 8.95-8.77 (m, 1H), 8.15 (d, J =5.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.63-7.52 (m, 2H), 7.47-7.14 (m,1H), 7.14-7.07 (m, 2H), 7.04 (dd, J = 1.2, 5.2 Hz, 1H), 6.98-6.84 (m,2H), 5.40-5.25 (m, 1H), 3.62-3.50 (m, 4H), 3.45 (s, 3H), 3.27 (s, 3H),3.18 (t, J = 6.4 Hz, 2H), 3.03-2.92 (m, 4H), 2.74 (s, 1H), 2.65-2.52 (m,2H), 2.09-1.92 (m, 1H), 1.90-1.60 (m, 4H), 1.12- 1.01 (m, 1H), 0.49-0.41(m, 2H), 0.26-0.19 (m, 2H) 470 I-475 PY FX 838.4 11.20 (s, 1H), 10.03(s, 1H), 8.97 (s, 1H), 8.91 (s, 1H), 8.57 (t, J = 5.6 Hz, 1H), 8.16 (d,J = 5.2 Hz, 1H), 8.04- 7.94 (m, 4H), 7.31 (t, J = 56 Hz, 1H), 7.15-7.06(m, 4H), 7.06-7.00 (m, 2H), 5.39-5.31 (m, 1H), 3.49- 3.40 (m, 6H), 3.18(t, J = 6.0 Hz, 2H), 2.93-2.82 (m, 1H), 2.76 (t, J = 7.6 Hz, 2H),2.68-2.60 (m, 2H), 2.20-2.10 (m, 1H), 1.91-1.84 (m, 2H), 1.83-1.76 (m,2H), 1.13-1.01 (m, 1H), 0.49-0.42 (m, 2H), 0.26- 0.19 (m, 2H) 471 I-476QA FX 852.5 11.18 (s, 1H), 10.12-9.91 (m, 1H), 8.98 (s, 1H), 8.85 (d, J= 17.2 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H),7.62-7.51 (m, 2H), 7.44-6.82 (m, 7H), 5.41-5.26 (m, 1H), 3.55-3.40 (m,4H), 3.39- 3.36 (m, 3H), 3.28-3.23 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H),2.99-2.92 (m, 3H), 2.89-2.75 (m, 2H), 2.20- 2.08 (m, 1H), 1.93-1.65 (m,4H), 1.11-1.02 (m, 1H), 0.49-0.41 (m, 2H), 0.26-0.19 (m, 2H) 472 I-477QI FX 865.4 11.07 (s, 1H), 10.12-9.87 (m, 1H), 8.97 (s, 1H), 8.92-8.72(m, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.65-7.48(m, 2H), 7.44-6.70 (m, 7H), 5.40-5.23 (m, 1H), 3.61-3.42 (m, 6H),3.32-3.23 (m, 6H), 3.21-3.18 (m, 2H), 2.98- 2.94 (m, 2H), 2.91-2.81 (m,1H), 2.69-2.60 (m, 2H), 2.04-1.93 (m, 1H), 1.92-1.61 (m, 4H), 1.12-1.02(m, 1H), 0.49-0.42 (m, 2H), 0.27- 0.19 (m, 2H) 473 I-478 QK FX 866.3(CDCl₃) 9.36 (s, 1H), 9.17 (s, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 8.24 (d,J = 5.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H),7.59 (s, 1H), 7.24-7.19 (m, 1H), 7.10- 6.81 (m, 4H), 6.71 (d, J = 7.2Hz, 1H), 5.20-5.12 (m, 1H), 3.74 (t, J = 5.3 Hz, 2H), 3.57-3.49 (m, 2H),3.25 (d, J = 5.6 Hz, 2H), 3.06-2.93 (m, 1H), 2.92-2.69 (m, 4H), 2.41-2.27 (m, 1H), 2.03-1.92 (m, 4H), 1.61 (s, 6H), 1.23-1.08 (m, 1H),0.69-0.57 (m, 2H), 0.39-0.29 (m, 2H) 474 I-479 PY FX 839.5 11.18 (s,1H), 10.08 (s, 1H), 9.11 (d, J = 2.4 Hz, 1H), 9.02 (s, 1H), 8.98 (s,1H), 8.87 (t, J = 6.0 Hz, 1H), 8.46 (dd, J = 2.4, 8.8 Hz, 1H), 8.21-8.14(m, 2H), 7.34 (d, J = 53.6 Hz, 1H), 7.14-7.00 (m, 6H), 5.34 (dd, J =5.6, 13.2 Hz, 1H), 3.47-3.41 (m, 6H), 3.20-3.17 (m, 2H), 2.89-2.81 (m,1H), 2.77 (t, J = 7.6 Hz, 2H), 2.70-2.64 (m, 2H), 2.17-2.09 (m, 1H),1.93-1.86 (m, 2H), 1.86-1.77 (m, 2H), 1.11-1.02 (m, 1H), 0.48- 0.43 (m,2H), 0.25-0.20 (m, 2H) 476 I-481 OD QW 983.3 11.07 (s, 1H), 10.98 (s,1H), 9.08 (s, 1H), 9.02 (s, 1H), 8.56 (t, J = 5.6 Hz, 1H), 8.26 (d, J =4.8 Hz, 1H), 8.00 (s, 4H), 7.67 (t, J = 6.4 Hz, 1H), 7.26 (s, 1H), .18(dd, J = 1.2, 5.2 Hz, 1H), 7.01 (s, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.85(d, J = 8.0 Hz, 1H), 5.38- 5.21 (m, 1H), 4.41-4.31 (s, 2H), 4.30-4.19(m, 2H), 3.81-3.80 (m, 2H), 3.32-3.26 (m, 11H), 2.96-2.81 (m, 1H),2.64-2.60 (m, 2H), 2.55- 2.52 (m, 5H), 2.47-2.42 (m, 4H), 2.23 (s, 3H),2.07-1.95 (m, 1H), 1.66-1.48 (m, 8H) 477 I-482 OD QY 971.5 11.07 (s,1H), 10.91 (s, 1H), 9.06 (s, 1H), 9.03 (s, 1H), 8.62-8.53 (m, 2H), 8.27(d, J = 5.2 Hz, 1H), 8.12- 8.05 (m, 2H), 8.04-7.99 (m, 2H), 7.69 (t, J =6.4 Hz, 1H), 7.27 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.03-6.97 (m, 2H),6.86 (d, J = 8.4 Hz, 1H), 5.32 (dd, J = 5.2, 12.8 Hz, 1H), 4.30- 4.21(m, 2H), 3.35-3.27 (m, 11H), 3.35-3.27 (m, 1H), 2.93-2.87 (m, 1H),2.65-2.58 (m, 4H), 2.57-2.54 (m, 2H), 2.22 (s, 6H), 2.05-1.96 (m, 1H),1.65-1.50 (m, 8H) 478 I-483 RD QZ 1001.6 9.36 (s, 1H), 8.93 (s, 1H),8.78 (d, J = 8.0 Hz, 1H), 8.52 (t, J = 6.0 Hz, 1H), 8.32 (s, 1H), 8.25(s, 1H), 7.80 (d, J = 9.6 Hz, 1H), 7.35 (q, J = 8.4 Hz, 4H), 7.09 (t, J= 56 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.08 (s, 1H), 4.49 (d, J = 9.6Hz, 1H), 4.44- 4.33 (m, 2H), 4.30 (s, 1H), 4.16 (dd, J = 5.6, 16.0 Hz,1H), 3.83 (s, 3H), 3.78 (s, 4H), 3.65-3.50 (m, 6H), 2.39 (s, 3H),2.35-2.28 (m, 2H), 2.27-2.15 (m, 1H), 2.10-1.94 (m, 2H), 1.90-1.80 (m,1H), 1.52-1.33 (m, 4H), 1.27-1.13 (m, 12H), 0.88 (s, 9H)  479^(b) I-484RD RA 1103.6 9.39 (s, 1H), 8.97 (s, 1H), 8.83 (d, J = (M + Na)⁺ 8.0 Hz,1H), 8.59 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.43-7.36 (m, 5H),7.27-6.97 (m, 1H), 6.91 (d, J = 7.6 Hz, 1H), 5.16 (d, J = 3.6 Hz, 1H),4.55 (d, J = 9.2 Hz, 1H), 4.42 (m, 2H), 4.37 (m, 2H), 4.26 (m, 1H), 4.21(s, 2H), 3.95 (s, 2H), 3.89-3.82 (m, 7H), 3.66-3.48 (m, 20H), 2.43 (s,4H), 2.05 (m, 1 H), 1.89 (m, 1H), 1.23 (m, 1H), 0.93 (s, 9H)  480^(b)I-485 RD RB 993.5 9.35 (s, 1H), 8.97-8.89 (m, 1H), 8.78 (d, J = 8.0 Hz,1H), 8.56 (t, J = 6.0 Hz, 1H), 8.32 (s, 1H), 8.29-8.23 (m, 1H),7.43-7.37 (m, 1H), 7.34 (s, 4H), 7.24-6.94 (m, 1H), 6.86 (d, J = 8.0 Hz,1H), 5.13 (d, J = 3.2 Hz, 1H), 4.51 (d, J = 9.6 Hz, 1H), 4.43- 4.28 (m,3H), 4.26-4.14 (m, 3H), 3.91 (s, 2H), 3.83 (s, 3H), 3.79 (s, 4H),3.61-3.50 (m, 15H), 2.40- 2.38 (m, 3H), 2.07-1.95 (m, 1H), 1.88-1.85 (m,1H), 0.86 (s, 9H)  482^(b) I-487 RR RP 934.4 11.07 (s, 1H), 10.04 (s,1H), 9.00 (s, 1H), 8.88 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.93 (d, J =7.6 Hz, 2H), 7.61 (t, J = 6.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H),7.46-7.30 (m, 1H), 7.26 (s, 1H), 7.21 (dd, J = 1.2, 5.2 Hz, 1H),7.08-6.96 (m, 2H), 6.92- 6.83 (m, 1H), 5.37-5.28 (m, 1H), 4.30-4.19 (m,2H), 3.88-3.69 (m, 2H), 3.70-3.58 (m, 1H), 3.57-3.46 (m, 3H), 3.31 (s,3H), 3.00 (s, 3H), 2.95-2.84 (m, 1H), 2.82-2.70 (m, 1H), 2.69-2.56 (m,4H), 2.36-2.31 (m, 1H), 2.27-2.20 (m, 1H), 2.09- 1.91 (m, 2H), 1.83-1.47(m, 3H)  483^(b) I-488 RW RU 906.2 11.08 (s, 1H), 10.05 (s, 1H), 8.97(s, 1H), 8.87 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.92 (s, 2H), 7.56 (d,J = 8.4 Hz, 2H), 7.30 (t, J = 54.8, 1H), 7.13-7.11 (m, 1H), 7.11-7.07(m, 1H), 7.06-6.95 (m, 3H), 6.90-6.83 (m, 1H), 5.43-5.20 (m, 1H), 3.88-3.67 (m, 4H), 3.28-3.22 (m, 5H), 3.19-3.17 (m, 2H), 2.99 (s, 3H),2.94-2.75 (m, 3H), 2.64-2.62 (m, 2H), 2.59-2.57 (m, 2H), 2.31-2.18 (m,2H), 2.10-1.93 (m, 2H), 1.79- 1.67 (m, 2H), 1.11-1.03 (m, 1H), 0.48-0.43(m, 2H), 0.24-0.20 (m, 2H) 484 I-489 RT CN 914.8 11.07 (s, 1H), 11.01(s, 1H), 9.01 (d, J = 8.4 Hz, 2H), 8.26 (d, J = 4.8 Hz, 1H), 8.16-8.00(m, 3H), 7.81-7.65 (m, 2H), 7.54 (s, 2H), 7.27 (s, 1H), 7.18 (d, J = 4.8Hz, 1H), 7.07-6.93 (m, 2H), 6.86-6.80 (m, 1H), 5.37- 5.27 (m, 1H),4.40-4.15 (m, 2H), 3.45-3.27 (m, 10H), 3.06-2.80 (m, 4H), 2.65-2.55 (m,4H), 2.03-1.96 (m, 1H), 1.68-1.36 (m, 8H)  485^(b) I-490 RR RU 906.511.07 (s, 1H), 10.03 (s, 1H), 8.98 (s, 1H), 8.88 (s, 1H), 8.16 (d, J =5.2 Hz, 1H), 7.93 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 7.30(t, J = 8.4 Hz, 1H), 7.12 (s, 1H), 7.08 (t, J = 5.6 Hz, 1H), 7.06-6.95(m, 3H), 6.92-6.82 (m, 1H), 5.37-5.28 (m, 1H), 3.88-3.76 (m, 2H),3.72-3.63 (m, 2H), 3.62-3.58 (m, 1H), 3.31 (s, 3H), 3.19 (t, J = 6.0 Hz,2H), 3.00 (s, 3H), 2.96-2.85 (m, 1H), 2.83-2.74 (m, 1H), 2.72-2.65 (m,2H), 2.63- 2.57 (m, 2H), 2.36-2.28 (m, 2H), 2.27-2.14 (m, , 1H),2.12-1.94 (m, 2H), 1.86-1.53 (m, 3H), 1.17-0.95 (m, 1H), 0.49-0.43 (m,2H), 0.25- 0.18 (m, 2H) 486 I-491 RT FX 893.5 11.08 (s, 1H), 10.04 (s,1H), 8.98 (s, 1H), 8.88 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.93 (d, J =8.4 Hz, 2H), 7.59-7.49 (m, 2H), 7.31 (t, J = 54 Hz, 1H), 7.13 (s, 1H),7.09 (t, J = 5.6 Hz, 1H), 7.06-7.04 (m, 1H), 6.99 (d, J = 7.6 Hz, 2H),6.85 (s, 1H), 5.40-5.25 (m, 1H), 3.52-3.39 (m, 4H), 3.31 (s, 6H),3.22-3.17 (m, 2H), 2.99-2.84 (m, 4H), 2.77-2.69 (m, 1H), 2.65-2.62 (m,1H), 2.61- 2.57 (m, 1H), 2.06-1.94 (m, 1H), 1.67-1.47 (m, 6H), 1.42-1.16(m, 2H), 1.10-1.01 (m, 1H), 0.49-0.44 (m, 2H), 0.26-0.21 (m, 2H) 489I-494 QI CN 886.6 11.14-10.87 (m, 2H), 9.09-8.83 (m, 2H), 8.27 (d, J =5.2 Hz, 1H), 8.14-8.00 (m, 3H), 7.78-7.67 (m, 2H), 7.54-7.63 (m, 2H),7.27 (s, 1H), 7.19 (d, J = 5.2 Hz, 1H), 7.12- 6.94 (m, 1H), 6.93-6.66(m, 2H), 5.40-5.17 (m, 1H), 4.31-4.21 (m, 2H), 3.57-3.37 (m, 6H),3.32-3.23 (m, 6H), 3.05-2.92 (m, 3H), 2.68- 2.91 (m, 2H), 2.08-1.98 (s,1H), 1.89-1.59 (m, 4H) 490 I-495 QA CN 873.6 11.19 (s, 1H), 10.99 (s,1H), 9.04 (s, 1H), 9.02-8.91 (m, 1H), 8.27 (d, J = 5.2 Hz, 1H),8.16-8.00 (m, 3H), 7.80-7.66 (m, 2H), 7.62-7.53 (m, 2H), 7.28 (s, 1H),7.19 (d, J = 5.6 Hz, 1H), 7.16-6.75 (m, 3H), 5.42- 5.24 (m, 1H),4.31-4.20 (m, 2H), 3.59-3.38 (m, 6H), 3.28-3.21 (m, 3H), 3.01-2.92 (m,3H), 2.90-2.73 (m, 2H), 2.20-2.12 (m, 1H), 1.91- 1.64 (m, 4H)  499^(b)I-504 SI RU 914.1 11.10 (s, 1H), 10.03 (s, 1H), 8.98 (s, 1H), 8.88 (s,1H), 8.16 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.62-7.48 (m, 2H),7.46-7.17 (m, 2H), 7.14-7.00 (m, 5H), 5.37 (dd, J = 4.8, 12.0 Hz, 1H),3.40-3.35 (m, 4H), 3.33 (s, 3H), 3.18 (t, J = 6.4 Hz, 2H), 2.95 (d, J =13.2 Hz, 4H), 2.88-2.69 (m, 2H), 2.71-2.57 (m, 4H), 2.12-1.93 (m, 3H),1.80-1.62 (m, 2H), 1.51- 1.48 (m, 1H), 1.25 (d, J = 12.0 Hz, 1H),1.11-1.02 (m, 1H), 0.95-0.80 (m, 1H), 0.49-0.42 (m, 2H), 0.26- 0.19 (m,2H) 501 I-506 SL FX 947.5 11.14-11.04 (m, 1H), 10.05 (s, 1H), 8.98 (s,1H), 8.93 (s, 1H), 8.76 (d, J = 6.8 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H),8.06-7.95 (m, 4H), 7.47-7.17 (m, 1H), 7.12 (s, 1H), 7.10-7.09 (m, 2H),7.06-7.04 (m, 1H), 7.03 (s, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.39- 5.32(m, 1H), 4.43 (d, J = 7.2 Hz, 1H), 4.14-4.10 (m, 1H), 3.47 (s, 2H),3.42-3.41 (m, 2H), 3.33 (s, 3H), 3.16-3.18 (m, 2H), 2.92-2.85 (m, 1H),2.77-2.70 (m, 1H), 2.70- 2.66 (m, 1H), 2.64-2.62 (m, 1H), 2.61-2.57 (m,2H), 2.56-2.53 (m, 3H), 2.47-2.44 (m, 4H), 2.30-2.24 (m, 4H), 2.06-1.97(m, 1H), 2.05- 1.97 (m, 1H), 1.12-1.02 (m, 1H), 0.48-0.42 (m, 2H),0.25-0.20 (m, 2H)  503^(b) I-508 SM RU 903.4 10.98 (d, J = 8.0 Hz, 1H),10.03 (s, 1H), 8.97 (s, 1H), 8.92 (s, 1H), 8.70 (s, 1H), 8.16 (d, J =5.2 Hz, 1H), 8.06-7.94 (m, 4H), 7.55-7.17 (m, 5H), 7.12 (s, 1H), 7.08(t, J = 5.6 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 5.72- 5.57 (m, 1H),4.76-4.61 (m, 1H), 3.97-3.82 (m, 2H), 3.69-3.63 (m, 1H), 3.59-3.50 (m,4H), 3.28-3.24 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.91-2.79 (m, 2H),2.71 (s, 1H), 2.60-2.53 (m, 2H), 2.40-2.33 (m, 1H), 2.26-2.17 (m, 1H),2.11 (t, J = 9.6 Hz, 1H), 2.04-1.92 (m, 1H), 1.11-1.03 (m, 1H),0.48-0.42 (m, 2H), 0.25-0.20 (m, 2H)  504^(b) I-509 SO RU 903.4 10.99(d, J = 5.6 Hz, 1H), 10.04 (s, 1H), 8.98 (s, 1H), 8.93 (s, 1H), 8.71 (,J = 5.6Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.06-8.02 (m, 2H), 8.00- 7.96(m, 2H), 7.50-7.41 (m, 4H), 7.40-7.18 (m, 1H), 7.12-7.07 (m, 2H), 7.04(dd, J = 1.2, 5.2 Hz, 1H), 5.72-5.58 (m, 1H), 4.75-4.61 (m, 1H),3.94-3.84 (m, 2H), 3.68-3.63 (m, 1H), 3.57 (s, 2H), 3.55-3.51 (m, 1H),3.26-3.21 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.88-2.81 (m, 2H),2.79-2.69 (m, 1H), 2.58-2.55 (m, 2H), 2.43-2.35 (m, 1H), 2.26-2.17 (m,1H), 2.14-2.07 (m, 1H), 2.02- 1.92 (m, 1H), 1.10-1.03 (m, 1H), 0.48-0.43(m, 2H), 0.24-0.21 (m, 2H)  508^(b) I-513 TT RU 906.6 11.08 (s, 1H),10.02 (s, 1H), 8.97 (s, 1H), 8.88 (s, 1H), 8.18-8.15 (m, 1H), 7.93-7.91(m, 2H), 7.56- 7.55(m, 2H), 7.47-7.15 (m, 1H), 7.14-7.02 (m, 3H),7.00-6.82 (m, 3H), 5.37-5.33 (m, 1H), 3.88-3.68 (m, 3H), 3.57 (d, J =2.8 Hz, 6H), 3.00 (s, 3H), 2.97-2.75 (m, 5H), 2.74-2.56 (m, 4H),2.35-2.26 (m, 2H), 2.05-1.92 (m, 2H), 1.83-1.66 (m, 2H), 1.13-1.02 (m,1H), 0.50- 0.40 (m, 2H), 0.26-0.18 (m, 2H) 509 I-514 TU FX 906.3 11.07(s, 1H), 10.01 (s, 1H), 8.96 (s, 1H), 8.87 (s, 1H), 8.18-8.11 (m, 1H),8.01-7.84 (m, 2H), 7.57 (s, 2H), 7.30 (t, J = 54.4 Hz, 1H), 7.11 (s,1H), 7.07 (t, J = 4.8 Hz, 1H), 7.03 (dd, J = 1.6 Hz, 1H), 7.00-6.80 (m,3H), 5.43-5.27 (m, 1H), 3.57 (s, 6H), 3.28 (s, 3H), 3.21-3.15 (t, J =6.0 Hz, 3H), 3.00 (s, 3H), 2.96-2.83 (m, 4H), 2.51 (s, 6H), 2.04-1.92(m, 2H), 1.11-1.01 (m, 1H), 0.50-0.39 (m, 2H), 0.26-0.17 (m, 2H) 510^(b) I-515 SV RU 895.5 10.02 (s, 1H), 8.97 (s, 1H), 8.89 (s, 1H),8.64 (t, J = 5.6 Hz, 1H), 8.16 (d, J = 5.2 Hz, 1H), 8.04-7.98 (m, 2H),7.97-7.91 (m, 2H), 7.31 (t, J = 54.4 Hz, 1H), 7.14-7.06 (m, 2H), 7.04(d, J = 5.2 Hz, 1H), 6.96-6.89 (m, 2H), 6.83 (dd, J = 1.6, 6.9 Hz, 1H),5.41 (dd, J = 5.2, 13.0 Hz, 1H), 3.60-3.56 (m, 4H), 3.55-3.53 (m, 4H),3.48-3.44 (m, 4H), 3.18 (t, J = 6.0 Hz, 2H), 3.02 (s, 3H), 2.92 (dd, J =7.2, 8.7 Hz, 3H), 2.80-2.73 (m, 1H), 2.03-1.95 (m, 1H), 1.84-1.76 (m,2H), 1.11-1.02 (m, 1H), 0.49- 0.42 (m, 2H), 0.23 (q, J = 4.8 Hz, 2H),−0.02-−0.12 (m, 2H) 512 I-517 WN FX 921.5 11.07 (s, 1H), 10.03 (s, 1H),8.98 (s, 1H), 8.87 (s, 1H), 8.16 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 8.8Hz, 2H), 7.56 (d, J = 8.8 Hz, 2H), 7.31 (t, J = 54 Hz, 1H), 7.12-6.98(m, 5H), 6.87 (d, J = 8.0 Hz, 1H), 5.35-5.31 (m, 1H), 4.06-3.85 (m, 1H),3.62- 3.55 (m, 3H), 3.53-3.49 (m, 2H), 3.44-3.39 (m, 2H), 3.35 (s, 3H),3.27 (m, 2H), 3.19 (t, J = 6.0 Hz, 2H), 2.93-2.84 (m, 1H), 2.77-2.69 (m,1H), 2.64 (m, 2H), 2.54 (m, 2H), 2.03-1.95 (m, 1H), 1.91-1.77 (m, 4H),1.55-1.40 (m, 2H), 1.11-1.01 (m, 1H), 0.50-0.40 (m, 2H), 0.24- 0.21 (m,2H) ^(a)Variations in reaction time for Method 12 were as follows: Step1 was run anywhere from 0.5-12 h, anc Step 2 anywhere from 10 min-17 h.If the product of Step 1 was not a precipitate, a standard work up withwater and extraction with ethyl acetate was used to isolate the product.Step 2 deprotection could also be achieved under a variety of standardconditions if not with HCl/dioxane in DCM, including with TFA in DCM atrt. ^(b)No Step 2 deprotection required. cStep 2 deprotection wasachieved using HBr/HOAc in DCM at rt for 12 h.

Further Examples Using Synthetic Methods Similar to Method 12 Example514:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-519

Step 1—Tert-ButylN-[4-[4-[[1-[4-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-ff(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a mixture of benzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(30.0 mg, 30.3 umol, TFA, Intermediate PJ) and DIPEA (19.6 mg, 151 umol,26.4 uL) in DMF (2 mL) was added4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicacid (18.0 mg, 30.3 umol, Intermediate FX) and HATU (13.8 mg, 36.4umol). The reaction mixture was stirred at 25° C. for 0.5 hour. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (0.1% FA condition) to give the title compound(25.0 mg, 56% yield) as white solid. LC-MS (ESI⁺) m/z 1451.8 (M+H)⁺.

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a mixture of tert-butylN-[4-[4-[[1-[4-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(30.0 mg, 20.6 umol) in THF (3 mL) was added Pd/C (30 mg, 10% wt). Thereaction mixture was stirred at 25° C. for 2 hours under H₂ (15 psi)atmosphere. On completion, the reaction mixture was filtered and thefiltrate concentrated in vacuo to give the title compound (27.0 mg, 99%yield) as light yellow oil. LC-MS (ESI⁺) m/z 1316.6 (M+H)¹.

Step3-2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]-4-carboxamide

To a mixture of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(27.0 mg, 20.5 umol) in DCM (3 mL) was added HCl/dioxane (4 M, 5.13 uL).The reaction mixture was stirred at 25° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 13%-43%, 10 min) to give the titlecompound (10.7 mg, 42% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 10.06 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 8.65 (t, J=5.2 Hz, 1H),8.33 (s, 1H), 8.20-8.15 (m, 2H), 8.06-7.95 (m, 4H), 7.95-7.84 (m, 1H),7.48-7.16 (m, 1H), 7.13-6.97 (m, 7H), 6.91 (d, J=2.4 Hz, 1H), 6.81-6.75(m, 1H), 4.99-4.81 (m, 2H), 4.79-4.61 (m, 2H), 4.08-4.01 (m, 2H), 3.73(d, J=3.6 Hz, 2H), 3.61-3.47 (m, 17H), 3.18 (t, J=6.0 Hz, 2H), 3.02-2.90(m, 3H), 2.74-2.62 (m, 2H), 2.16 (s, 1H), 2.12 (s, 2H), 1.89-1.73 (m,2H), 1.72-1.62 (m, 1H), 1.60-1.50 (m, 1H), 1.12-0.99 (m, 10H), 0.98-0.88(m, 3H), 0.48-0.43 (m, 2H), 0.26-0.20 (m, 2H). LC-MS (ESI⁺) m/z 1216.6(M+H)⁺.

Example 515:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-pyrazol-4-yl]oxazole-4-carboxamide,I-520

Step 1—Tert-ButylN-[4-[4-[[1-[4-[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl]amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]eythoxy]eythoxy]eythoxy]eythoxy]ethylcarbamoyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a mixture of benzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2-2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(70.0 mg, 76.2 umol, Intermediate WE),4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoic acid (45.3 mg, 76.2 umol,Intermediate FX) in DMF (2 mL) was added DIPEA (29.6 mg, 229 umol) andHATU (34.8 mg, 91.5 umol). The reaction mixture was stirred at 20° C.for 1 hour. On completion, the reaction mixture was poured into water(20 mL). The aqueous phase was extracted with ethyl acetate (2×20 mL).The combined organic phase was washed with brine (2×30 mL), dried withanhydrous Na₂SO₄, filtered and concentrated in vacuo to give residue.The residue was purified by reverse phase (0.1% FA condition) to givethe title compound (70 mg, 57% yield) as black solid. LC-MS (ESI⁺) m/z1494.9 (M+H)⁺.

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a mixture of tert-butylN-[4-[4-[[1-[4-[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethylcarbamoyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(35.0 mg, 23.4 umol) in THF (2 mL) was added Pd/C (20 mg, 20% wt). Thesuspension was degassed under vacuum and purged with H₂ three times. Thereaction mixture was stirred under H₂ (15 psi) at 20° C. for 1 hour. Oncompletion, the reaction mixture was filtered and concentrated in vacuoto give the title compound (32.0 mg, crude quant. yield) as brown solid.LC-MS (ESI⁺) m/z 1360.6 (M+H)⁺.

Step3—2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide

To a mixture of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(32.0 mg, 23.5 umol) in DCM (5 mL) was added HCl/dioxane (4 M, 2 mL).The reaction mixture was stirred at 20° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo to give the residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 16%-46%, 10min) to give the title compound (8 mg, 6.17 umol, 26% yield) as a greensolid. LC-MS (ESI⁺) m/z 1260.9 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.07(s, 1H), 9.03-8.90 (m, 2H), 8.66 (s, 1H), 8.25-8.13 (m, 2H), 8.07-7.85(m, 5H), 7.48-7.17 (m, 1H), 7.16-6.99 (m, 8H), 6.92 (s, 1H), 6.82-6.77(m, 1H), 5.01-4.82 (m, 2H), 4.80-4.61 (m, 2H), 4.05 (s, 2H), 3.73 (s,2H), 3.58-3.51 (m, 18H), 3.19-3.17 (m, 4H), 3.00-2.97 (m, 4H), 2.69-2.68(m, 3H), 2.22-2.04 (m, 3H), 1.92-1.74 (m, 2H), 1.73-1.51 (m, 3H),1.14-1.00 (m, 10H), 0.94 (s, 2H), 0.47-0.45 (m, 2H), 0.23-0.22 (m, 2H).

Example 516:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]-phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-521

Step 1—Tert-ButylN-[4-[4-[[1-[4-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl]carbamate

To a solution of benzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(50 mg, 52.9 umol, TFA, Intermediate PF) and4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicacid (31.5 mg, 52.9 umol, Intermediate FX) in DMF (3 mL) was added DIPEA(34.2 mg, 264 umol, 46.1 uL) and HATU (24.1 mg, 63.5 umol). The mixturewas stirred at 25° C. for 1.5 hr. On completion, the reaction mixturewas quenched with H₂O (1 mL) and then concentrated in vacuo to give aresidue. The residue was purified by reverse phase (0.1% FA condition)to give the title compound (40 mg, 53% yield) as a white solid. LC-MS(ESI⁺) m/z 1406.7 (M+H)⁺.

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]-phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-[4-[4-[[1-[4-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]-phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(40.0 mg, 28.4 umol) in THF (5 mL) was added Pd/C (20 mg, 10% wt), thereaction mixture was stirred at 25° C. for 40 mins under H₂. Oncompletion, the mixture was filtered. The filtrate was concentrated invacuo to give the title compound (35 mg, 96% yield) as a yellow solid.LC-MS (ESI⁺) m/z 1272.8 (M+H)⁺.

Step3-2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]-phenyl]pyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylcarbamoyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(35.0 mg, 27.5 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 2 mL),the reaction mixture was stirred at 20° C. for 1 hr. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 15%-45%, 10min) to give the title compound (23.0 mg, 71% yield, FA) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.97 (s, 1H), 8.91 (s,1H), 9.71-8.60 (m 1H), 8.21-8.13 (m, 2H), 8.04-8.00 (m, 2H), 7.99-7.95(s, 2H), 7.94-7.85 (m, 1H), 7.45-7.17 (m, 1H), 7.14-7.00 (m, 8H),6.91-6.76 (m, 2H), 5.09-4.47 (m, 6H), 4.06-4.01 (m, 2H), 3.74-3.68 (m,2H), 3.55 (s, 9H), 3.48-3.45 (m, 2H), 3.18 (t, J=6.0 Hz, 2H), 3.03-2.91(m, 4H), 2.73-2.64 (, 2H), 2.16 (s, 1H, 2.11 (s, 2H), 1.88-1.73 (9, 2H),1.70-1.63 (m, 1H), 1.60-1.50 (m, 1H), 1.11-1.02 (m, 10H), 0.93 (s, 3n),0.47-0.42 (m 2n), 0.24-0.20 (m 2n); LC-MS (ESI⁺) m/z 172.8 (M+).

TABLE 23 Compounds synthesized via Method 16 with the reductiveamination of various amines with aldehydes in Step 1 LCMS Step 1 Step 1(ES+) Intermediate Intermediate m/z Ex-# I-# Amine Aldehyde (M + H)⁺1HNMR (400 MHz, DMSO-d6) δ 517 I-522 UE LS 915.4 11.08 (s, 1H), 10.8 (s,1H), 8.89 (s, 1H), 8.29-8.20 (m, 2H), 8.10 (s, 1H), 7.61- 7.50 (m, 2H),7.25-7.16 (m, 2H), 7.12 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H),6.59 (t, J = 5.6 Hz, 1H), 5.07-5.04 (m, 1H), 4.32-4.16 (m, 2H), 3.95 (s,2H), 3.79 (s, 3H), 3.53-3.41 (m, 22H), 2.94-2.82 (m, 1H), 2.77 (t, J =5.6 Hz, 2H), 2.64-2.53 (m, 2H), 2.08-1.97 (m, 1H) 518 I-523 WI GF 865.411.10 (s, 1H), 10.01 (s, 1H), 8.98 (s, 1H), 8.80 (s, 1H), 8.24 (s, 1H),8.17 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz,2H), 7.45- 7.15 (m, 1H), 7.14-7.08 (m, 2H), 7.07- 7.02 (m, 1H),6.99-6.92 (m, 2H), 6.88-6.85 (m, 1H), 5.37 (dd, J = 5.6, 12.8 Hz, 1H),3.81 (s, 2H), 3.56 (s, 3H), 3.34-3.29 (m, 4H), 3.27-3.15 (m, 2H),2.96-2.86 (m, 3H), 2.77-2.58 (m, 4H), 2.04-1.94 (m, 1H), 1.68- 1.49 (m,8H), 1.13-1.00 (m, 1H), 0.50- 0.42 (m, 2H), 0.27-0.19 (m, 2H) 519 I-524LP LS 984.3 10.83 (s, 1H), 8.97 (s, 1H), 8.90 (s, 1H), 8.56 (s, 1H),8.22 (s, 2H), 8.10 (s, 1H), 7.56 (s, 1H), 7.40 (s, 5H), 7.21 (s, 2H),4.58-4.49 (m, 1H), 4.43-4.36 (m, 1H), 4.34 (s, 1H), 4.26-4.24 (m, 2H),3.95 (s, 2H), 3.85-3.75 (m, 1H), 3.79 (s, 3H), 3.70-3.58 (m, 14H), 3.20-3.16 (m, 1H), 3.07 (s, 2H), 3.15-2.98 (m, 1H), 2.77 (s, 2H), 2.64-2.59(m, 1H), 2.48-2.40 (m, 4H), 1.93-1.89 (m, 1H), 0.89 (s, 9H) 520 I-525 VELS 922.4 11.10 (s, 1H), 10.75-10.60 (m, 1H), 8.97-8.83 (m, 1H),8.25-8.13 (m, 2H), 7.60-7.38 (m, 1H), 7.30-7.10 (m, 2H), 7.02-6.81 (m,3H), 5.41- 5.30 (m, 1H), 4.39-4.04 (m, 6H), 3.78 (s, 3H), 3.64-3.54 (m,4H), 3.52-3.49 (m, 3H), 2.99-2.77 (m, 13H), 2.72- 2.62 (m, 2H),2.28-2.16 (m, 3H), 2.08 (s, 1H), 2.02-1.94 (m, 1H), 1.91-1.72 (m, 2H)521 I-526 VH GY 1027.5 11.06-10.07 (m, 1H), 10.16-9.95 (m, 1H), 9.01 (d,J = 2.4 Hz, 2H), 8.25 (d, J = 5.2 Hz, 1H), 8.16-7.97 (m, 3H), 7.83- 7.67(m, 3H), 7.50-7.37 (m, 1H), 7.35-7.24 (m, 2H), 7.22-7.15 (m, 1H),7.13-6.95 (m, 2H), 6.92-6.81 (m, 1H), 5.38-5.27 (m, 1H), 4.50- 3.99 (m,6H), 3.27-3.20 (m, 4H), 3.02- 2.65 (m, 15H), 2.37-1.69 (m, 3H),1.58-1.39 (m, 1H), 1.23 (s, 4H), 1.20- 1.14 (m, 1H), 0.85 (t, J = 6.4Hz, 1H)  522^(b) I-527 HQ VI 749.0 11.70-11.64 (m, 1H), 11.06 (s, 1H),9.24 (s, 2H), 9.07 (s, 1H), 9.01 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H), 8.18(d, J = 4.8 Hz, 1H), 8.06-8.04 (m, 2H), 7.80- 7.68 (m, 3H), 7.00-6.89(m, 2H), 6.85- 6.82 (m, 1H), 5.38-5.30 (m, 1H), 4.28- 4.20 (m, 2H),3.80-3.70 (m, 2H), 3.65- 3.51 (m, 9H), 3.19-3.08 (m, 2H), 2.99-2.82 (m,3H), 2.74-2.57 (m, 2H), 2.04-1.91 (m, 1H), 1.88-1.77 (m, 2H) 523 I-528HQ VM 885.4 11.07 (s, 1H), 8.84 (s, 1H), 8.77 (s, 1H), 8.22 (d, J = 1.6Hz, 1H), 7.73-7.67 (m, 2H), 7.56 (t, J = 6.4 Hz, 1H), 7.41 (d, J = 8.6Hz, 2H), 7.25 (s, 1H), 7.18 (dd, J = 1.2, 5.2 Hz, 1H), 6.98-6.91 (m,2H), 6.92-6.82 (m, 1H), 5.39-5.32 (m, 1H), 4.28-4.17 (m, 4H), 3.77 (s,2H), 3.55 (s, 3H), 3.54-3.51 (m, 6H), 3.47- 3.44 (m, 2H), 2.97-2.92 (m,2H), 2.92- 2.85 (m, 1H), 2.82 (t, J = 6.4 Hz, 2H), 2.70 (t, J = 5.6 Hz,2H), 2.68-2.56 (m, 2H), 2.08-2.01 (m, 2H), 2.01-1.95 (m, 1H), 1.86-1.77(m, 2H) 524 I-529 VO GF 910.5 10.99 (s, 1H), 10.01 (s, 1H), 8.97 (s,1H), 8.79 (s, 1H), 8.32 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.80 (d, J =8.4 Hz, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H),7.44-7.38 (m, 2H), 7.31- 7.15 (m, 1H), 7.13-7.08 (m, 2H), 7.05 (d, J =5.2 Hz, 1H), 6.59 (, J = 5.6 Hz, 1H), 6.09-6.04 (m, 1H), 5.15- 5.05 (m,1H), 4.42-4.30 (m, 4H), 3.77 (s, 2H), 3.56-3.52 (m, 12H), 3.22- 3.17 (m,2H), 2.95-2.90 (m, 1H), 2.69- 2.66(m, 1H), 2.43-2.30 (m, 1H), 2.05- 1.94(m, 1H), 1.27-1.11 (m, 1H), 0.49-0.43 (m, 2H), 0.26-0.21 (m, 2H) 525I-530 RI GF 823.1 11.07 (s, 1H), 9.97 (s, 1H), 8.96 (s, 1H), 8.79 (s,1H), 8.19 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H),7.51 (d, J = 8.4 Hz, 2H), 7.44-7.14 (m, 1H), 7.12 (s, 1H), 7.08 (t, J =5.6 Hz, 1H), 7.04 (dd, J = 1.6, 5.2 Hz, 1H), 6.99- 6.93 (m, 2H),6.90-6.84 (m, 1H), 5.36 (dd, J = 5.2, 12.4 Hz, 1H), 3.84 (s, 2H), 3.56(s, 3H), 3.52-3.48 (m, 2H), 3.47-3.44 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H),2.99-2.94 (m, 2H), 2.90-2.82 (m, 1H), 2.74 (t, J = 5.2 Hz, 2H), 2.70-2.57 (m, 2H), 2.03-1.94 (m, 1H), 1.90- 1.79 (m, 2H), 1.12-1.02 (m, 1H),0.49-0.43 (m, 2H), 0.26-0.20 (m, 2H) 526 I-531 RH GF 823.4 11.09 (s,1H), 10.01 (s, 1H), 8.96 (s, 1H), 8.79 (s, 1H), 8.21 (s, 1H), 8.15 (d, J= 52 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.44-7.14 (m, 1H), 7.13-7.07 (m, 2H), 7.06- 7.02 (m, 2H), 7.00 (d, J = 8.0Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.37-5.28 (m, 1H), 3.86 (s, 2H),3.40-3.38 (m, 4H), 3.31 (s, 3H), 3.18 (t, J = 6.0 Hz, 2H), 2.94-2.84 (m,1H), 2.76 (t, J = 5.6 Hz, 2H), 2.71-2.66 (m, 2H), 2.65-2.54 (m, 2H),2.05-1.94 (m, 1H), 1.89- 1.77 (m, 2H), 1.13-1.00 (m, 1H), 0.50- 0.41 (m,2H), 0.25-0.20 (m, 2H) 527 I-532 RH JC 951.4 11.07 (s, 1H), 9.98 (s,1H), 8.99 (s, 1H), 8.79 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.81 (d, J =7.6 Hz, 2H), 7.61 (t, J = 6.4 Hz, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.43-7.15 (m, 3H), 7.06-6.97 (m, 2H), 6.87 (d, J = 7.6 Hz, 1H), 5.33 (dd, J =5.2, 12.8 Hz, 1H), 4.30-4.19 (m, 2H), 3.81 (s, 2H), 3.55-3.44 (m, 7H),2.96-2.83 (m, 1H), 2.71-2.64 (m, 4H), 2.60- 2.53 (m, 2H), 2.04-1.96 (m,1H), 1.90- 1.85 (m, 2H) 528 I-533 RI JC 851.1 11.08 (s, 1H), 9.99 (s,1H), 8.99 (s, 1H), 8.80 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.16 (s, 1H),7.83 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 6.8 Hz, 1H), 7.53 (d, J = 8.4 Hz,2H), 7.44-7.15 (m, 3H), 6.99- 6.93 (m, 2H), 6.90-6.84 (m, 1H), 5.36 (dd,J = 5.2, 12.4 Hz, 1H), 4.32-4.19 (m, 2H), 3.87 (s, 2H), 3.56 (s, 3H),3.52 (t, J = 5.2 Hz, 2H), 3.49-3.46 (t, J = 6.4 Hz, 2H), 3.01-2.94 (m,2H), 2.91- 2.82 (m, 1H), 2.77 (t, J = 5.6 Hz, 2H), 2.72-2.58 (m, 2H),2.03-1.94 (m, 1H), 1.90-1.78 (m, 2H) 529 I-534 LG JC 865.4 11.07 (s,1H), 9.99 (s, 1H), 8.99 (s, 1H), 8.78 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H),7.81 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 6.4 Hz, 1H), 7.51 (d, J = 8.4 Hz,2H), 7.43-7.14 (m, 3H), 7.05-6.94 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H),5.32 (dd, J = 5.2, 12.8 Hz, 1H), 4.29-4.20 (m, 2H), 3.81 (s, 2H), 3.43(t, J = 6.0 Hz, 2H), 3.36 (t, J = 6.0 Hz, 2H), 3.31 (s, 3H), 2.93-2.83(m, 1H), 2.75-2.57 (m, 6H), 2.05-1.95 (m, 1H), 1.86- 1.75 (m, 2H),1.75-1.65 (m, 2H) 530 I-535 LF JC 865.4 11.08 (s, 1H), 10.10 (d, J = 2.0Hz, 1H), 9.06 (s, 1H), 8.87 (s, 1H), 8.26 (d, J = 5.6 Hz, 1H), 8.09-7.91(m, 3H), 7.81- 7.76 (m, 2H), 7.48-7.17 (m, 3H), 7.02- 6.91 (m, 2H),6.89-6.78 (m, 1H), 5.39-5.35 (m, 1H), 4.37-4.29 (m, 2H), 4.22 (m, 3H),3.56 (d, J = 4.8 Hz, 3H), 3.50-3.44 (m, 4H), 3.13-2.79 (m, 5H), 2.70 (d,J = 4.8 Hz, 2H), 2.62 (d, J = 8.8 Hz, 1H), 2.07-1.93 (m, 3H), 1.88- 1.75(m, 2H)  531^(c) I-536 OS GF 934.5 11.08 (s, 1H), 10.16 (s, 1H), 8.95(s, 1H), 8.77 (s, 1H), 8.30 (s, 2H), 8.16 (d, J = 5.2 Hz, 1H), 7.79 (d,J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.43- 7.14 (m, 2H), 7.11 (s,1H), 7.10-6.93 (m, 4H), 6.88 (d, J = 3.6 Hz, 1H), 5.35- 5.33 (m, 1H),4.31 (s, 2H), 3.81-3.79 (m, 11H), 3.22-3.12 (m, 2H), 2.93- 2.91 (m, 4H),2.72-2.59 (m, 2H), 2.59- 2.58 (m, 2H), 2.59-2.57 (m, 1H), 2.39-2.36 (m,1H), 2.29-2.26 (m, 2H), 2.01-1.98 (m, 1H), 1.79 1.76 (m, 2H), 1.9-1.06(m, 1H), 0.48-0.44 (m, 2H), 0.50-0.40 (m, 1H), 0.24-0.21 (m, 2H) 532^(c) I-537 OV GF 934.5 11.10 (s, 1H), 10.23 (s, 1H), 9.55 (s, 1H),9.14 (s, 1H), 9.07 (s, 1H), 8.89 (s, 1H), 8.11 (d, J = 6.4 Hz, 1H), 7.96(d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.56 (s, 1H), 7.49-7.18(m, 3H), 7.13- 7.02 (m, 2H), 6.91 (d, J = 8.0 Hz, 1H), 5.43-5.30 (m,1H), 4.55-4.43 (m, 2H), 4.30-4.17 (m, 2H), 3.94-3.81 (m, 2H), 3.76-3.46(m, 2H), 3.34 (s, 3H), 3.30-3.21 (m, 4H), 3.05-2.95 (m, 2H), 2.94-2.85(m, 4H), 2.85- 2.80 (m, 1H), 2.75-2.69 (m, 2H), 2.65- 2.59 (m, 2H),2.06-1.92 (m, 3H), 1.20-1.07 (m, 1H), 0.60-0.50 (m, 2H), 0.35-0.27 (m,2H) 533 I-538 PA OX 829.3 11.22 (s, 1H), 10.70 (s, 1H), 9.02 (s, 1H),8.88-8.78 (m, 1H), 8.24 (s, 1H), 8.17 (d, J = 5.2 Hz, 1H), 7.83 (d, J =8.4 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.25 (s, 1H), 7.18-7.01 (m, 5H),5.34 (d, J = 5.6, 13.2 Hz, 1H), 3.79 (s, 2H), 3.57- 3.47 (m, 5H),3.24-3.15 (m, 2H), 2.70- 2.61 (m, 7H), 2.37-2.31 (m, 2H), 2.21-2.08 (m,1H), 2.21-2.07 (m, 2H), 1.78 (d, J = 7.2 Hz, 2H), 1.12- 0.98 (m, 1H),0.52-0.40 (m, 2H), 0.29- 0.17 (m, 2H) 534 I-539 VR VZ 885.5 11.09 (s,1H), 9.99 (s, 1H), 8.97 (s, 1H), 8.84 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H),7.75-7.67 (m, 2H), 7.64-7.55 (m, 1H), 7.29 (t, J = 54.0 Hz, 1H), 7.12(s, 1H), 7.10-7.06 (m, 1H), 7.05-7.03 (m, 1H), 7.02-7.00 (m, 1H), 7.00-6.96 (m, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.32 (dd, J = 5.2, 12.8 Hz, 1H),3.80 (s, 2H), 3.56-3.47 (m, 6H), 3.42-3.37 (m, 2H), 3.30 (s, 3H), 3.19(t, J = 6.0 Hz, 2H), 2.94-2.83 (m, 1H), 2.74- 2.57 (m, 6H), 2.03-1.95(m, 1H), 1.85- 1.74 (m, 2H), 1.12-1.02 (m, 1H), 0.49-0.42 (m, 2H),0.26-0.20 (m, 2H)  535^(b) I-540 PD PB 865.3 10.85 (s, 1H), 9.78 (s,1H), 8.73 (s, 1H), 8.57 (s, 1H), 8.07 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H),7.61 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.05 (t, J = 54 Hz,1H), 6.88 (s, 1H), 6.85-6.80 (m, 2H), 6.80-6.74 (m, 2H), 6.63 (d, J =7.2 Hz, 1H), 5.15-5.05 (m, 1H), 3.67 (s, 2H), 3.09 (s, 3H), 3.00-2.92(m, 2H), 2.72-2.60 (m, 1H), 2.49-2.37 (m, 4H), 2.36-2.31 (m, 2H), 1.82-1.71 (m, 1H), 1.40-1.21 (m, 4H), 1.18- 1.07 (m, 4H), 1.02-0.84 (m, 1H),0.79 (s, 3H), 0.25-0.19 (m, 2H), 0.02- 0.04 (m, 2H) 536 I-541 HQ WJ860.4 11.10 (s, 1H), 9.87 (s, 1H), 8.90 (s, 1H), 8.73 (d, J = 2.0 Hz,1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.22 (d, J = 5.2 Hz, 1H), 8.03 (s, 1H),7.99 (s, 1H), 7.58 (t, J = 6.8 Hz, 1H), 7.22 (s, 1H), 7.19 (d, J = 5.26Hz, 1H), 6.94 (d, J = 6.4 Hz, 2H), 6.86-6.81 (m, 1H), 5.37-5.34 (m, 1H), 4.27-4.17 (m, 2H), 3.91 (s, 3H), 3.75 (s, 2H), 3.52 (s, 3H),3.46-3.42 (m, 8H), 2.91-2.89 (m, 3H), 2.64- 2.58 (m, 4H), 1.99-1.98 (m,1H), 1.79 (m, 2H) 537 I-542 PH PG 836.5 11.61-10.80 (m, 1H), 10.02 (s,1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.29 (s, 2H), 8.16 (d, J = 5.2 Hz, 1H),7.83 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.43- 7.15 (m, 2H),7.13-7.02 (m, 5H), 5.42- 5.30 (dd, J = 5.4, 12.7 Hz, 1H), 3.91 (s, 2H),3.85-3.83 (m, 2H), 3.39-3.28 (m, 3H), 3.18 (t, J = 6.4 Hz, 2H), 2.96-2.84 (m, 1H), 2.77-2.68 (m, 2H), 2.68- 2.64 (m, 2H), 2.64-2.58 (d, J =6.8 Hz, 2H), 2.04-1.94 (m, 1H), 1.58- 1.42 (m, 4H), 1.38-1.26 (m, 2H),1.17- 0.97 (m, 1H), 0.50-0.41 (m, 2H), 0.28-0.19 (m, 2H) 538 I-543 WH GF852.3 11.09 (s, 1H), 10.00 (s, 1H), 8.97 (s, 1H), 8.79 (s, 1H), 8.55 (t,J = 6.0 Hz, 1H), 8.20-8.12 (m, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.49 (d, J= 8.4 Hz, 2H), 7.43-7.15 (m, 1H), 7.13-7.08 (m, 2H), 7.07-7.02 (m, 3H),6.95 (d, J = 8.4 Hz, 1H), 5.34 (dd, J = 5.6, 12.8 Hz, 1H), 4.34 (d, J =6.0 Hz, 2H), 3.95 (s, 2H), 3.82 (s, 2H), 3.59-3.57 (m, 2H), 3.30 (s,3H), 3.21-3.14 (m, 2H), 2.93- 2.84 (m, 1H), 2.77 (t, J = 5.2 Hz, 2H),2.71-2.57 (m, 2H), 2.04-1.93 (m, 1H), 1.13-1.01 (m, 1H), 0.49-0.41 (m,2H), 0.27-0.19 (m, 2H) 539 I-544 SV GY 902.5 11.02 (s, 1H), 9.03 (s,1H), 8.96 (s, 1H), 8.26 (d, J = 5.2 Hz, 1H), 8.06 (s, 1H), 8.00 (d, J =8.4 Hz, 2H), 7.76 (s, 1H), 7.71 (t, J = 6.4 Hz, 1H), 7.60 (d, J = 8.4Hz, 2H), 7.27 (s, 1H), 7.17 (dd, J = 1.2, 5.2 Hz, 1H), 6.98-6.89 (m,2H), 6.84 (dd, J = 1.2, 7.2 Hz, 1H), 5.47-5.38 (m, 1H), 4.31-4.19 (m,2H), 4.09 (s, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.61- 3.58 (m, 2H),3.58-3.56 (m, 2H), 3.55 (s, 3H), 3.47 (t, J = 6.0 Hz, 2H), 3.01 (s, 3H),2.99-2.91 (m, 4H), 2.80-2.74 (m, 1H), 2.72-2.52 (m, 2H), 2.05- 1.95 (m,1H), 1.88-1.75 (m, 2H) 540 I-545 PL GF 852.4 11.09 (s, 1H), 9.99 (s,1H), 8.97 (s, 1H), 8.79 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.81 (d, J =8.4 Hz, 2H), 7.63 (t, J = 5.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.27(t, J = 7.6 Hz, 1H), 7.11 (s, 1H), 7.10- 7.01 (m, 4H), 6.94 (d, J = 7.6Hz, 1H), 5.34 (dd, J = 5.2, 12.8 Hz, 1H), 4.19 (d, J = 5.6 Hz, 2H), 4.04(t, J = 6.4 Hz, 2H), 3.80 (s, 2H), 3.31 (s, 3H), 3.18 (t, J = 6.0 Hz,2H), 2.94-2.86 (m, 1H), 2.73- 2.60 (m, 2H), 2.55-2.52 (m, 2H), 2.04-1.94(m, 1H), 1.81-1.70 (m, 2H), 1.11-1.02 (m, 1H), 0.48-0.42 (m, 2H),0.25-0.19 (m, 2H) 544 I-549 PZ GF 824.2 11.15 (s, 1H), 9.93 (s, 1H),8.91 (s, 1H), 8.72 (s, 1H), 8.21 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.75(d, J = 8.8 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.38-7.17 (m, 2H),7.12-7.03 (m, 3H), 7.01-6.94 (m, 2H), 5.28 (d, J = 5.2, 12.8 Hz, 1H),3.72 (s, 2H), 3.19-3.09 (m, 8H), 2.89- 2.76 (m, 2H), 2.62 (d, J = 2.0,3.6 Hz, 4H), 2.58-2.52 (m, 5H), 2.32-2.25 (m, 2H), 2.09 (td, J = 5.2,10.4 Hz, 1H), 1.78-1.68 (m, 2H), 1.64 (d, J = 6.5 Hz, 2H), 1.07-0.96 (m,1H), 0.45-0.37 (m, 2H), 0.21-0.14 (m, 2H) 545 I-550 PA GF 854.4 11.16(s, 1H), 9.97 (s, 1H), 8.95 (s, 1H), 8.77 (s, 1H), 8.20 (s, 1H), 8.15(d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H),7.42-7.10 (m, 4H), 7.08-6.99 (m, 3H), 5.32 (dd, J = 5.2, 12.8 Hz, 1H),3.83 (s, 2H), 3.55- 3.52 (m, 2H), 3.50-3.48 (m, 6H), 3.18 (t, J = 6.0Hz, 2H), 2.95-2.81 (m, 1H), 2.75-2.70 (m, 2H), 2.68-2.60 (m, 4H),2.19-2.08 (m, 1H), 1.82-1.73 (m, 2H), 1.08-1.06 (m, 1H), 0.51- 0.40 (m,2H), 0.24-0.20 (m, 2H) 546 I-551 JG GF 854.3 11.21 (s, 1H), 10.00 (s,1H), 8.97 (s, 1H), 8.77 (s, 1H), 8.25 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H),7.78 (d, J = 8.4 Hz, 2H), 7.54-7.45 (m, 2H), 7.29 (t, J = 54 Hz 1H),7.14-7.06 (m, 4H), 7.05-7.02 (m, 1H), 7.01-6.97 (m, 1H), 5.35 (dd, J =5.2, 12.8 Hz, 1H), 3.80 (s, 2H), 3.53- 3.49 (m, 8H), 3.18 (t, J = 6.0Hz, 2H), 2.91-2.84 (m, 1H), 2.75-2.65 (m, 6H), 2.17-2.10 (m, 1H),1.88-1.77 (m, 2H), 1.12-1.03 (m, 1H), 0.50- 0.42 (m, 2H), 0.26-0.18(m,2H) 547 I-552 QC GF 839.4 11.08 (s, 1H), 9.97 (s, 1H), 8.95 (s, 1H),8.78 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.48(d, J = 8.8 Hz, 2H), 7.42-7.14 (m, 2H), 7.12- 6.98 (m, 6H), 5.39-5.32(m, 1H), 3.99 (t, J = 5.6 Hz, 2H), 3.78 (s, 2H), 3.69 (t, J = 5.6 Hz,2H), 3.55-3.52 (m, 2H), 3.47-3.45 (m, 4H), 3.18 (t, J = 6.0 Hz, 2H),2.95-2.83 (m, 1H), 2.69-2.58 (m, 4H), 2.06-1.96 (m, 1H), 1.12- 1.01 (m,1H), 0.49-0.42 (m, 2H), 0.26- 0.19 (m, 2H) 567 I-572 RJ GY 899.4 11.09(s, 1H), 11.01 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.25 (d, J = 4.8 Hz,1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.97- 7.86 (m, 2H), 7.80-7.65 (m, 2H),7.53- 7.46 (m, 2H), 7.26 (s, 1H), 7.17 (d, J = 4.8 Hz, 1H), 7.04 (s,1H), 6.99 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.33 (dd, J =5.2, 12.8 Hz, 1H), 4.29- 4.20 (m, 2H), 3.85-3.73 (m, 3H), 3.59- 3.55 (m,2H), 3.31 (s, 3H), 2.95-2.77 (m, 2H), 2.69-2.56 (m, 7H), 2.27 (t, J =6.4 Hz, 2H), 2.02-1.93 (m, 2H), 1.79- 1.68 (m, 3H) 568 I-573 RJ GF 878.511.07 (s, 1H), 9.98 (s, 1H), 8.95 (s, 1H), 8.78 (s, 1H), 8.16 (d, J =1.6 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.28(t, J = 54.4 Hz, 1H), 7.11 (s, 1H), 7.09-7.03 (m, 3H), 6.99 (d, J = 8.0Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 5.35-5.29 (m, 1H), 3.82 (s, 2H), 3.78(d, J = 11.6 Hz, 1H), 3.55-3.53 (m, 1H), 3.31 (s, 3H), 3.20-3.17 (m,2H), 2.93-2.86 (m, 1H), 2.81 (d, J = 11.2 Hz, 1H), 2.72-2.57 (m, 9H),2.28 (t, J = 7.2 Hz, 2H), 2.03-1.93 (m, 2H), 1.79- 1.70 (m, 3H),1.12-1.01 (m, 1H), 0.49-0.42 (m, 2H), 0.25-0.19 (m, 2H) 569 I-574 RK GF878.2 11.08 (s, 1H), 10.00 (s, 1H), 8.97 (s, 1H), 8.79 (s, 1H),8.19-8.14 (m, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H),7.44-7.14 (m, 1H), 7.13- 7.07 (m, 2H), 7.06-7.01 (m, 2H), 6.99 (d, J =8.0 Hz, 1H), 6.90-6.83 (m, 1H), 5.37-5.28 (m, 1H), 3.79 (s, 2H), 3.76(s, 1H), 3.31 (s, 3H), 3.17 (d, J = 6.2 Hz, 2H), 2.94-2.79 (m, 3H),2.72- 2.56 (m, 9H), 2.28 (t, J = 7.2 Hz, 2H), 2.03-1.92 (m, 2H),1.79-1.67 (m, 3H), 1.12-0.98 (m, 1H), 0.49-0.38 (m, 2H), 0.26-0.17 (m,2H) 570 I-575 RM GY 913.5 11.22-10.08 (m, 2H), 9.02 (s, 1H), 8.92 (s,1H), 8.31-8.23 (m, 3H), 7.91 (d, J = 8.8 Hz, 2H), 7.76-7.67 (m, 2H),7.50 (d, J = 8.8 Hz, 2H), 7.27 (s, 1H), 7.20-7.15 (m, 1H), 7.08-6.96 (m,2H), 6.89-6.84 (d, 1H), 5.42-5.27 (m, 1H), 4.29-4.17 (m, 2H), 3.96-3.67(m, 3H), 3.35-3.33 (m, 2H), 3.31 (s, 3H), 3.25-3.18 (m, 2H), 2.91-2.84(m, 1H), 2.90-2.84 (m, 2H), 2.63- 2.59 (m, 4H), 2.26 (t, J = 6.8 Hz,1H), 2.12-1.88 (m, 2H), 1.79-1.66 (m, 2H), 1.62-1.50 (m, 2H) 571 I-576RO GY 913.5 11.08 (s, 1H), 11.00 (s, 1H), 9.02 (s, 1H), 8.93 (s, 1H),8.25 (d, J = 5.2 Hz, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.74-7.66 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.26 (s, 1H),7.19-7.16 (m, 1H), 7.04 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.87 (d, J =8.0 Hz, 1H), 5.35-5.30 (m, 1 H), 4.28-4.21 (m, 2H), 3.83 (s, 2H),3.75-3.73 (m, 1H), 3.45-3.44 (m, 3H), 3.31 (s, 3H), 2.91-2.87 (m, 1H),2.72 (m, 2H), 2.65- 2.59 (m, 5H), 2.27-2.25 (m, 2H), 2.06-1.88 (m, 3H),1.77-1.65 (m, 3 H), 1.59 (m, 2H) 573 I-578 RT GY 900.5 11.08 (s, 1H),11.01 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.26 (d, J = 5.2 Hz, 1H),8.05 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.76-7.67 (m, 2H), 7.44 (d, J =8.8 Hz, 2H), 7.27 (s, 1H), 7.18 (dd, J = 1.2, 5.2 Hz, 1H), 7.06-6.96 (m,2H), 6.89-6.81 (m, 1H), 5.33 (dd, J = 52, 12.8 Hz, 1H), 4.31-4.19 (m,2H), 3.49 (s, 2H), 3.31 (s, 3H), 2.95-2.83 (m, 1H), 2.77-2.53 (m, 8H),2.38-2.30 (m, 2H), 2.13 (s, 3H), 2.04-1.96 (m, 1H), 1.67-1.58 (m, 2H),1.55-1.46 (m, 6H) 574 I-579 QN GY 932.4 11.00 (s, 1H), 11.00-10.87 (m,1H), 9.01 (s, 1H), 8.91 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.02 (s, 1H),7.95-7.84 (m, 3H), 7.68 (dd, J = 7.2, 11.2 Hz, 3H), 7.53-7.43 (m, 3H),7.38 (d, J = 7.6 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H),5.14-5.06 (m, 1H), 4.48- 4.37 (m, 1H), 4.33-4.17 (m, 5H), 4.12- 4.04 (m,2H), 3.77 (s, 2H), 3.59 (s, 2H), 3.51 (dd, J = 5.6, 9.2 Hz, 6H), 2.98-2.84 (m, 1H), 2.67 (d, J = 5.2 Hz, 2H), 2.59 (d, J = 19.6 Hz, 2H),2.43-2.35 (m, 1H), 2.03-1.93 (m, 1H) 575 I-580 TP GF 862.4 10.99 (s,1H), 10.03 (s, 1H), 8.93 (m, 1H), 8.81 (s, 1H), 8.33-8.08 (m, 2H), 7.88(d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.2 Hz, 2H), 7.46-7.02 (m, 8H), 5.70-5.57 (m, 1H), 4.69-4.60 (m, 1H), 4.05 (s, 2H), 3.94-3.86 (m, 4H), 3.23(t, J = 8.0 Hz, 2H), 3.19-3.15 (m, 2H), 2.92- 2.87 (m, 2H), 2.82-2.77(m, 1H), 2.68- 2.64 (m, 2H), 2.59-2.56 (m, 1H), 2.23-2.16 (m, 1H),2.00-1.92 (m, 1H), 1.88-1.80 (m, 2H), 1.10-1.01 (m, 1H), 0.49-0.41 (m,2H), 0.26- 0.17 (m, 2H) 576 I-581 SF GF 862.4 10.02 (s, 1H), 8.97 (s,1H), 8.80 (s, 1H), 8.25 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.82 (d, J =8.4 Hz, 2H), 7.58-7.46 (m, 3H), 7.46-7.39 (m, 4H), 7.32-7.13 (m, 1H),7.13-7.08 (m, 2H), 7.05 (d, J = 5.2 Hz, 1H), 5.71-5.58 (m, 1H), 4.76-4.73 (m, 1H), 3.90-3.84 (m, 2H), 3.52-3.50 (m, 4H), 3.27-3.21 (m, 2H),3.20-3.17 (m, 2H), 2.91-2.77 (m, 1H), 2.70-2.64 (m, 4H), 2.60- 2.56 (m,1H), 2.28-2.16 (m, 1H), 2.03- 1.93 (m, 1H), 1.78-1.71 (m, 2H), 1.12-1.03(m, 1H), 0.49-0.44 (m, 2H), 0.25-0.21 (m, 2H)  577^(b) I-582 YY PB 886.611.11 (s, 1H), 9.98 (s, 1H), 8.96 (s, 1H), 8.78 (s, 1H), 8.16 (d, J =5.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H),7.31-7.00 (m, 7H), 5.41- 5.31 (m, 1H), 3.74 (s, 3H), 3.30-3.25 (m, 2H),3.20-3.16 (m, 2H), 2.95- 2.82 (m, 3H), 2.65-2.54 (m, 7H), 2.39- 2.35 (m,2H), 2.00-1.91 (m, 2H), 1.76-1.65 (m, 2H), 1.46-1.31 (m, 1H), 1.18-1.01(m, 3H), 0.50-0.40 (m, 2H), 0.26-0.18(m, 2H) 578 I-583 SL GF 933.6 11.09(s, 1H), 9.99 (s, 1H), 8.96 (s, 1H), 8.78 (s, 1H), 8.15 (d, J = 5.2 Hz,1H), 7.79 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.42-7.14 (m,1H), 7.09 (d, J = 10 Hz, 3H), 7.05-7.01 (m, 2H), 6.98- 6.92 (m, 1H),5.34 (dd, J = 5.2, 12.8 Hz, 1H), 4.11-4.01 (m, 2H), 3.65 (s, 3H),3.45-3.45 (m, 2H), 3.29-3.28 (m, 2H), 3.19-3.16 (m, 4H), 2.96- 2.83 (m,3H), 2.75-2.69 (m, 1H), 2.64- 2.57 (m, 4H), 2.44-2.41 (m, 6H), 2.29-2.25(m, 1H), 2.01-1.99 (m, 4H), 1.09-1.02 (m, 1H), 0.49-0.42 (m, 2H),0.26-0.19 (m, 2H) 579 I-584 SM GF 889.4 11.00 (s, 1H), 9.97 (s, 1H),8.97 (s, 1H), 8.78 (s, 1H), 8.23 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 7.79(d, J = 8.4 Hz, 2H), 7.55-7.43 (m, 6H), 7.28 (t, J = 54.4 Hz, 2H), 7.12(s, 1H), 7.08 (t, J = 5.2 Hz, 1H), 7.04 (d, J = 5.2 Hz, 1H), 5.71- 5.59(m, 1H), 4.73-4.62 (m, 1H), 3.93 (t, J = 8.8 Hz, 1H), 3.86 (d, J = 8.8Hz, 1H), 3.82 (d, J = 10.8 Hz, 1H), 3.76 (s, 2H), 3.61-3.52 (m, 2H),3.28-3.23 (m, 2H), 3.18 (t, J = 6.0 Hz, 2H), 2.90- 2.77 (m, 2H),2.69-2.66 (m, 1H), 2.65- 2.55 (m, 2H), 2.35-2.32 (m, 1H), 2.31-2.12 (m,2H), 2.07 (t, J = 10.4 Hz, 1H), 2.01-1.92 (m, 1H), 1.12- 1.02 (m, 1H),0.49-0.42 (m, 2H), 0.26- 0.20 (m, 2H) 580 I-585 SO GF 889.4 11.00 (s,1H), 10.02 (s, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 8.15 (d, J = 5.6 Hz,1H), 7.79 (d, J = 8.4 Hz, 2H), 7.52- 7.45 (m, 5H), 7.43-7.14 (m, 2H),7.12- 7.08 (m, 2H), 7.04 (d, J = 4.8 Hz, 1H), 5.72-5.59 (m, 1H),4.73-4.61 (m, 1H), 3.96-3.78 (m, 3H), 3.76 (s, 2H), 3.58-3.52 (m, 2H),3.26-3.14 (m, 5H), 2.92-2.73 (m, 3H), 2.64-2.57 (m, 2H), 2.31-2.25 (m,1H), 2.23- 2.14 (m, 1H), 2.09-2.02(m, 1H), 2.01- 1.91 (m, 1H), 1.10-1.02(m, 1H), 0.48- 0.43 (m, 2H), 0.24-0.19 (m, 2H) 582 I-587 SQ GF 878.411.08 (s, 1H), 9.99 (s, 1H), 8.96 (s, 1H), 8.79 (s, 1H), 8.18-8.15 (m,2H), 7.86- 7.77 (m, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.43-7.14 (m, 1H),7.11 (s, 1H), 7.08 (t, J = 5.6 Hz, 1H), 7.05-7.02 (m, 1H), 6.99-6.85 (m,3H), 5.36 (dd, J = 5.6, 12.0 Hz, 1H), 3.84-3.78 (m, 3H), 3.77- 3.74,3.57 (s, 3H), 3.18 (t, J = 6.0 Hz, 2H), 2.95-2.83 (m, 4H), 2.71-2.54 (m,6H), 2.36-2.32 (m, 2H), 2.04- 1.93 (m, 2H), 1.82-1.67 (m, 3H), 1.14-1.00 (m, 1H), 0.51-0.37 (m, 2H), 0.25-0.19 (m, 2H) 583 I-588 SR GF 878.211.09 (s, 1H), 9.99 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.16 (d, J =5.6 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H),7.45-7.13 (m, 1H), 7.13- 7.06 (m, 2H), 7.04 (dd, J = 1.2, 5.2 Hz, 1H),6.98-6.92 (m, 2H), 6.91-6.85 (m, 1H), 5.37 (dd, J = 5.2, 12.4 Hz, 1H),3.87-3.69 (m, 4H), 3.62-3.45 (m, 6H), 3.18 (t, J = 6.0 Hz, 2H), 3.04-2.79 (m, 4H), 2.76-2.58 (m, 4H), 2.42- 2.23 (m, 2H), 2.04-1.93 (m, 2H),1.81-1.71 (m, 3H), 1.13-1.01 (m, 1H), 0.51-0.40 (m, 2H), 0.26-0.18 (m,2H) 584 I-589 SS GF 865.0 11.20 (s, 1H), 9.98 (s, 1H), 8.96 (s, 1H),8.78 (s, 1H), 8.16 (d, J = 5.4 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.48(d, J = 8.7 Hz, 2H), 7.29 (s, 1H), 7.16-7.06 (m, 4H), 7.05-7.01 (m, 2H),5.40-5.28 (m, 1H), 3.76 (s, 2H), 3.51 (d, J = 2.4 Hz, 2H), 3.20-3.15 (m,3H), 2.90- 2.78 (m, 2H), 2.75-2.61 (m, 6H), 2.56 (d, J = 6.5 Hz, 1H),2.36-2.26 (m, 3H), 2.18-2.11 (m, 1H), 2.01-1.92 (m, 1H), 1.83-1.69 (m,3H), 1.11-1.02 (m, 1H), 0.49-0.42 (m, 2H), 0.25- 0.19 (m, 2H) 585 I-590ST GF 865.4 δ 11.20 (s, 1H), 9.99 (s, 1H), 8.96 (s, 1H), 8.78 (s, 1H),8.19-8.15 (m, 2H), 7.86-7.75 (m, 2H), 7.50 (d, J = 8.0 Hz, 2H),7.44-6.99 (m, 7H), 5.42-5.30 (m, 1H), 3.84-3.72 (m, 4H), 3.18 (t, J =6.0, 2H), 2.90-2.79 (m, 2H), 2.75- 2.54 (m, 8H), 2.34-2.31 (m, 2H),2.18- 2.12 (m, 1H), 2.01-1.94 (m, 1H), 1.85-1.69 (m, 3H), 1.12-1.02 (m,1H), 0.49-0.41 (m, 2H), 0.26-0.18 (m, 2H) 586 I-591 TW GF 906.5 11.08(s, 1H), 9.99 (s, 1H), 8.98 (s, 1H), 8.80 (s, 1H), 8.16 (d, J = 5.2 Hz,1H), 8.13 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H),7.29 (s, 1H), 7.13-7.07 (m, 2H), 7.05-7.02 (m, 2H), 6.99 (d, J = 8.0 Hz,1H), 6.87 (d, J = 8.0 Hz, 1H), 5.36-5.30 (m, 1H), 3.77- 3.71 (m, 1H),3.63-3.53 (m, 2H), 3.51-3.43 (m, 3H), 3.31 (s, 3H), 3.20- 3.16 (m, 2H),2.94-2.83 (m, 1H), 2.80- 2.68 (m, 2H), 2.65-2.58 (m, 3H), 2.55-2.53 (m,2H), 2.32-2.25 (m, 2H), 2.24-2.13 (m, 3H), 2.04-1.92 (m, 2H), 1.82-1.69(m, 3H), 1.68- 1.55 (m, 2H), 1.12-1.00 (m, 1H), 0.50- 0.42 (m, 2H),0.26-0.19 (m, 2H) 587 I-592 TY GF 906.2 11.09 (s, 1H), 10.01 (s, 1H),8.97 (s, 1H), 8.78 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.80 (d, J = 8.4Hz, 2H), 7.47- 7.14 (m, 3H), 7.14-7.07 (m, 2H), 7.07- 7.01 (m, 2H),7.01-6.94 (m, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.32 (dd, J = 5.2, 12.8 Hz,1H), 3.77-3.68 (m, 2H), 3.49 (s, 2H), 3.31 (s, 3H), 3.18 (t, J = 6.0 Hz,2H), 2.92-2.84 (m, 1H), 2.77-2.68 (m, 2H), 2.64-2.56 (m, 5H), 2.43- 2.39(m, 2H), 2.25 (t, J = 7.2 Hz, 2H), 2.12 (s, 3H), 2.01-1.89 (m, 2H),1.78- 1.64 (m, 3H), 1.61-1.51 (m, 2H), 1.09- 1.03 (m, 1H), 0.51-0.38 (m,2H), 0.27-0.17 (m, 2H) 588 I-593 SQ GY 899.4 11.08 (s, 1H), 11.00 (s,1H), 9.02 (s, 1H), 8.97 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 8.13 (s, 1H),8.09-7.96 (m, 3H), 7.75 (s, 1H), 7.69 (t, J = 6.4 Hz, 1H), 7.59 (d, J =8.4 Hz, 2H), 7.26 (s, 1H), 7.17 (dd, J = 5.2 Hz, 1H), 6.95 (d, J = 4.8Hz, 2H), 6.90-6.85 (m, 1H), 5.39- 5.32 (m, 1H), 4.29-4.19 (m, 2H), 4.03(s, 1H), 3.88-3.79 (m, 1H), 3.73-3.61 (m, 2H), 3.57 (s, 3H), 3.53-3.50(m, 1H), 2.95-2.80 (m, 7H), 2.76-2.68 ( m, 2H), 2.65-2.62 (m , 1H),2.61-2.58 (m, 1H), 2.41-2.35 (m, 2H), 2.10- 1.94 (m, 2H), 1.78-1.73 (m,2H) 590 I-595 SU GF 888.4 10.86 (s, 1H), 9.75 (s, 1H), 8.73 (s, 1H),8.53 (s, 1H), 8.17 (dd, J = 1.6, 8.0 Hz, 1H), 8.09 (dd, J = 1.6, 4.8 Hz,1H), 8.05 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 2H),7.24 (d, J = 8.8 Hz, 2H), 7.20-7.04 (m, 3H), 6.94-6.88 (m, 3H), 6.85 (t,J = 5.6 Hz, 1H), 6.83- 6.79 (m, 1H), 6.68 (dd, J = 2.0, 8.8 Hz, 1H),5.73-5.59 (m, 1H), 3.54 (s, 2H), 3.44.3.40 (m, 2H), 3.38-3.32 (m, 8H),3.06-3.02 (m, 2H), 2.96-29.4 (m, 2H), 2.77-2.73 (m, 1H), 2.48- 2.46 (m,1H), 2.43-2.40 (m, 1H), 1.84- 1.82 (m, 1H), 0.26-0.20 (m, 2H), 0.10-0.02(m, 2H) 591 I-596 SV GF 881.5 9.97 (s, 1H), 8.95 (s, 1H), 8.75 (s, 1H),8.15 (d, J = 5.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 2H), 7.45-7.51 (m, 2H),7.13- 7.42 (t, J = 5.2 Hz, 1H), 7.06-7.12 (m, 2H), 7.03 (dd, J = 5.2 Hz,1H), 6.89- 6.97 (m, 2H), 6.83 (s, 1H), 5.41-5.38 (m, 1H), 3.78 (s, 2H),3.54 (s, 3H), 3.51- 3.53 (m, 6H), 3.45-3.40 (m, 4H), 3.17 (d, J = 6.4Hz, 2H), 3.01 (s, 3H), 2.94 (d, J = 6.4 Hz, 2H), 2.73-2.80 (m, 2H),2.69-2.71 (m, 2H), 2.66-2.68 (m, 2H), 1.95-2.02 (m, 1H), 1.77- 1.84 (m,2H), 1.03-1.10 (m, 1H), 0.42- 0.47 (m, 2H), 0.19-0.23 (m, 2H) 592 I-5972-(2-methoxy- GF 603.3 11.01 (s, 1H), 9.03 (s, 1H), 8.99 (s, 1H),ethoxy)-ethan- 8.26 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 8.4 amine (CAS#Hz, 3H), 7.77 (s, 1H), 7.70 (t, J = 6.4 31576-51-9) Hz, 1H), 7.64 (d, J= 8.8 Hz, 2H), 7.26 (s, 1H), 7.18 (d, J = 5.2 Hz, 1H), 4.28- 4.20 (m,2H), 4.15 (s, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.59-3.56 (m, 2H), 3.49-3.47 (m, 2H), 3.26 (s, 3H), 3.05 (t, J = 5.2 Hz, 2H) 593 I-598 RR GF892.5 11.09 (s, 1H), 10.02 (s, 1H), 8.97 (s, 1H), 8.82 (s, 1H), 8.16 (d,J = 5.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H),7.30 (t, J = 8.4 Hz, 1H), 7.14-7.08 (m, 2H), 7.07-7.00 (m, 3H),6.92-6.86 (m, 1H), 5.34 (dd, J = 5.2, 12.4 Hz, 1H), 3.90-3.85 (m, 1H),3.82-3.76 (m, 2H), 3.64-3.59 (m, 2H), 3.32 (s, 3H), 3.20-3.17 (m, 2H),3.07-3.03 (m, 1H), 2.97-2.92 (m, 1H), 2.91-2.85 (m, 1H), 2.76-2.70 (m,1H), 2.69-2.57 (m, 7H), 2.57- 2.53 (m, 2H), 2.33 (s, 3H), 2.03-1.96 (m,1H), 1.89-1.80 (m, 2H), 1.12- 1.02 (m, 1H), 0.49-0.43 (m, 2H), 0.25-0.20 (m, 2H) 594 I-599 SZ GF 892.2 11.08 (s, 1H), 10.00 (s, 1H), 8.96(s, 1H), 8.78 (s, 1H), 8.22 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.80 (d,J = 8.4 Hz, 2H), 7.45 (d, J = 0.8 Hz, 2H), 7.12 (t, J = 14.8 Hz, 1H),7.10-7.06 (m, 1H), 7.05-7.03 (m, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.87 (m,1H), 5.35-5.30 (m, 1H), 3.75 (d, J = 11.6 Hz, 1H), 3.61 (s, 1H), 3.58(s, 2H), 3.31 (s, 3H), 3.18 (t, J = 6.0 Hz, 3H), 2.95-2.84 (m, 2H), 2.81(d, J = 10.8 Hz, 1H), 2.76-2.68 (m , 1H), 2.69-2.66 (m , 1H), 2.63 (d, J= 6.4 Hz, 3H), 2.40-2.38 (m, 1H), 2.35- 2.31 (m, 1H), 2.31-2.24 (m, 2H),2.18 (s, 3H), 2.02-1.96 (m, 1H), 1.95-1.89 (m, 1H), 1.78-1.72 (m, 2H),1.68 (t, J = 10.8 Hz, 1H), 1.12-1.01 (m, 1H), 0.48-0.42 (m, 2H),0.25-0.19 (m, 2H) 609 I-614 RK JC 906.5 11.09 (s, 1H), 10.08 (s, 1H),9.00 (s, 1H), 8.87 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.95 (d, J = 8.8Hz, 2H), 7.69- 7.61 (m, 3H), 7.44-7.17 (m, 3H), 7.07- 6.98 (m, 2H), 6.87(d, J = 8.8 Hz, 1H), 5.33 (dd, J = 5.2, 12.8 Hz, 1H), 4.28- 4.16 (m,4H), 3.94-3.77 (m, 2H), 3.68- 3.9 (m, 2H), 3.32 (s, 3H), 3.06-3.04 (m,2H), 3.00-2.78 (m, 5H), 2.74- 2.55 (m, 6H), 2.03-1.95 (m, 1H), 1.82-1.74 (m, 2H) 612 I-617 RK TA 866.5 11.07 (s, 1H), 9.49 (s, 1H), 8.97 (s,1H), 8.80 (d, J = 8.0 Hz, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.79 (d, J =8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.43-7.10 (m, 1H), 7.03 (s, 1H),6.99 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz,1H), 5.35-5.26 (m, 1H), 3.84- 3.75 (m, 7H), 3.48-3.46 (m, 4H), 3.31 (s,3H), 2.94-2.89 (m, 4H), 2.88- 2.79 (m, 2H), 2.70-2.66 (m, 1H), 2.64-2.59 (m, 4H), 2.58-2.55 (m, 1H), 2.54-2.52 (m, 1H), 2.31-2.22 (m, 2H),2.04-1.92 (m, 2H), 1.78-1.67 (m, 3H) ^(a)For Method 16, when the amineis the HCl salt, TEA was added to free base the salt, followed by HOActo adjust the pH to 3-4. KOAc could also be used in place of theTEA/HOAc combination. Other standard deprotections conditions could beused for the deprotection in Step 2, including often with TFA. Steps 1-2was run anywhere from 0.5-48 hrs. ^(b)No deprotection Step 2 required.^(c)In Step 1, Intermediates OS and were heated at 80° C. for 1 hr withHOAc and 4A MS, then NaBH3CN was added and the reaction mixture wasstirred at rt for 1 h. ^(d)In Step 2, the deprotection was achievedusing HBr/HOAc in THF at rt for 96-160 hrs. For Example 617, I-622 thereaction was run in DCM with HBr/HOAc for 12 hr. ^(e)In Step 2, thedeprotection was achieved using ZnBr₂ in DCM at rt.

Further Examples Using Synthetic Methods Similar to Method 16 Example675:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-680

Step 1—Tert-ButylN-[4-[4-[[1-[4-[[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxyl-ethylamino]methyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution ofbenzyl-N-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(100 mg, 96.9 umol, TFA, Intermediate WE) andtert-butyl-N-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(56.1 mg, 96.9 umol; Intermediate GF) in THF (4 mL) was added KOAc (19.0mg, 194 umol) and NaBH(OAc)₃ (41.1 mg, 194 umol). The reaction mixturewas stirred at 25° C. for 17 hrs. On completion, the mixture wasconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (90.0 mg, 63% yield) as a whitesolid. LC-MS (ESI⁺) m/z 1481.7 (M+H)⁺.

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-[4-[4-[[1-[4-[[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethylamino]methyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethylcarbamate(40 mg, 27.0 umol) in THF (5 mL) was added Pd(OH)₂/C (0.1 g, 20% wt).The reaction mixture was stirred at 25° C. for 2 hrs under H₂ (15 psi)atmosphere. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by reverse phase (0.1%FA condition) to give the title compound (35.0 mg, 96% yield) as a whitesolid. LC-MS (ESI⁺) m/z 1346.8 (M+H)⁺.

Step3-2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]-ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(30.0 mg, 22.3 umol) in DCM (2 mL) was added HCl/dioxane (2 mL). Thereaction mixture was stirred at 25° C. for 2 hrs. On completion, themixture was concentrated in vacuo. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 12%-39%, 9 min) to give the title compound (4.00mg, 14% yield, FA) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.00(s, 1H), 8.96 (s, 1H), 8.78 (s, 1H), 8.28-8.25 (m, 1H), 8.20-8.10 (m,2H), 8.03-7.89 (m, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H),7.29 (t, J=54.8 Hz 1H), 7.12-7.01 (m, 7H), 6.90 (s, 1H), 6.80-6.77 (m,1H), 5.19-4.86 (m, 2H), 4.78-4.62 (m, 2H), 4.10-4.00 (m, 2H), 3.80 (s,2H), 3.75-3.70 (m, 2H), 3.61-3.50 (m, 21H), 3.18 (t, J=6.0 Hz, 2H),3.09-3.02 (m, 1H), 3.01-2.92 (m, 2H), 2.76-2.63 (m, 4H), 2.21-2.12 (m,3H), 1.92-1.72 (m, 2H), 1.70-1.49 (m, 2H), 1.10 (d, J=6.8 Hz, 3H),1.07-1.05 (m, 1H), 1.05-0.91 (m, 9H), 0.50-0.41 (m, 2H), 0.27-0.18 (m,2H); LC-MS (ESI⁺) m/z 1246.8 (M+H)⁺.

Example 676:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-681

Step 1—Tert-ButylN-[4-[4-[[1-[4-[[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate

To a solution of benzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(150 mg, 158 umol, TFA, Intermediate PF) and tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(91.9 mg, 158 umol, Intermediate GF) in THF (30 mL) was added TEA (16.0mg, 158 umol, 22.1 uL). The mixture was stirred at 20° C. for 30 mins,then HOAc (25.6 mg, 426 umol, 24.3 uL) and NaBH(OAc)₃ (67.3 mg, 317umol) was added into the mixture, and the reaction mixture was stirredat 20° C. for 48 hrs. On completion, the reaction mixture was quenchedwith H₂O (0.5 mL) and then concentrated in vacuo to give a residue. Theresidue was purified by reverse phase chromatography (0.1% FA condition)to give the title compound (90 mg, 40% yield) as a white solid. LC-MS(ESI⁺) m/z 1392.3 (M+H)⁺.

Step 2—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate

To a solution of tert-butylN-[4-[4-[[1-[4-[[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]-3-(difluoromethyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(cyclopropylmethyl)carbamate(70.0 mg, 50.2 umol) in THF (1 mL) was added Pd(OH)₂/C (50 mg, 3.59umol, 10% wt), and the reaction mixture was stirred at 25° C. for 40 minunder H₂ gas (15 Psi). On completion, the mixture was filtered, thefiltrate was concentrated in vacuo to give the residue, and the residuewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 32%-50%, 6 min) to give thetitle compound (20 mg, 31% yield) as a yellow solid. LC-MS (ESI⁺) m/z1258.8 (M+H)⁺.

Step3-2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(20 mg, 15.8 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 1 mL), andthe reaction mixture was stirred at 25° C. for 1 hr. On completion, thereaction mixture was concentrated in vacuo to give a residue. Theresidue was purified by prep-HPLC (column: Shim-pack C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B3%: 12%-42%, 10 min) to give thetitle compound (1.57 mg, 8.0% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 10.01 (s, 1H), 8.92 (s, 1H), 8.74 (s, 1H), 8.33 (s, 2H),8.20-8.09 (m, 2H), 8.02-7.87 (m, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.52-7.42(m, 2H), 7.25 (t, J=54.8 Hz, 1H), 7.11-6.92 (m, 8H), 6.90-6.73 (m, 2H),4.96-4.82 (m, 2H), 4.74-4.58 (m, 2H), 4.05-3.99 (m, 2H), 3.78 (s, 3H),3.73-3.69 (m, 4H), 3.67-3.61 (m, 9H), 3.16 (t, J=6.0 Hz, 2H), 3.05-2.91(m, 3H), 2.70-2.65 (m, 4H), 2.20-2.15 (m, 1H), 2.13 (s, 2H), 1.89-1.71(m, 2H), 1.70-1.61 (m, 1H), 1.59-1.52 (m, 1H), 1.11-1.05 (m, 3H),1.04-0.89 (m, 9H), 0.47-0.41 (m, 2H), 0.24-0.18 (m, 2H); LC-MS (ESI⁺)m/z 1158.7 (M+H)⁺.

Example 677:N-[3-[[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-1-methyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-682

Step 1—Tert-ButylN-[4-[4-[[3-[[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of benzylN-[(1S)-2-[[(1S)-1-[(3S)-7-[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carbonyl]-2,2-dimethyl-propyl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate(55.0 mg, 55.7 umol, TFA, Intermediate PJ) and tert-butylN-[4-[4-[(3-formyl-1-methyl-pyrazol-4-yl)carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(27.5 mg, 55.7 umol, Intermediate LS) in a mixed solvent of DMF (1 mL)and THF (5 mL) was added KOAc (10.9 mg, 111 umol). The mixture wasstirred at 25° C. for 0.5 hour. NaBH(OAc)₃ (23.6 mg, 111 umol) was thenadded into the mixture and the reaction mixture was stirred at 25° C.for 24 hours. On completion, the mixture was concentrated in vacuo. Theresidue was purified by reverse phase chromatography (0.1% FA condition)to give the title compound (35.0 mg, 46% yield) as a brown solid. LC-MS(ESI⁺) m/z 1352.7 (M+H)⁺.

Step 2—Tert-ButylN-[4-[4-[[3-[[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

To a solution of tert-butylN-[4-[4-[[3-[[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-2-[[(2S)-2-[benzyloxycarbonyl(methyl)amino]propanoyl]amino]-3,3-dimethyl-butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(30.0 mg, 22.2 umol) in THF (3 mL) was added Pd(OH)₂/C (0.05 g, 20% wt).The reaction mixture was stirred at 25° C. for 1 hour under H₂ (15 Psi)atmosphere. On completion, the mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by reverse phasechromatography (0.1% FA condition) to give the title compound (15.0 mg,56% yield) as a yellow solid. LC-MS (ESI⁺) m/z 1218.8 (M+H)⁺.

Step3—N-[3-[[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-1-methyl-pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-[[2-[2-[2-[2-[2-[[(3S)-2-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-[[(1R)-tetralin-1-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-7-yl]oxy]ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]methyl]-1-methyl-pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(14.0 mg, 11.5 umol) in DCM (3 mL) was added HC/dioxane (3 mL). Thereaction mixture was stirred at 25° C. for 2 hours. On completion, themixture was concentrated in vacuo. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 17%-41%, 8 min) to give the title compound (2.00mg, 15% yield, FA) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.92(s, 1H), 8.88 (s, 1H), 8.25-8.18 (m, 2H), 8.13-8.10 (m, 1H), 7.98-7.88(m, 1H), 7.61-7.54 (m, 1H), 7.20 (s, 1H), 7.18-7.16 (m, 1H), 7.12-7.07(m, 2H), 7.07-7.01 (m, 2H), 6.89 (s, 1H), 6.82-6.72 (m, 2H), 5.23-4.92(m, 2H), 4.90-4.80 (m, 2H), 4.71-4.60 (m, 2H), 4.29-4.18 (m, 3H),4.05-3.97 (m, 2H), 3.92 (s, 2H), 3.79-3.56 (m, 16H), 3.00-2.93 (m, 3H),2.75-2.71 (m, 2H), 2.20-2.04 (m, 6H), 1.90-1.73 (m, 2H), 1.71-1.60 (m,2H), 1.57-1.49 (m, 1H), 1.13-1.07 (m, 3H), 1.07-1.04 (m, 1H), 1.03-0.92(m, 9H); LC-MS (ESI⁺) m/z 1118.7 (M+H)⁺.

Further Examples Example 679:2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-684

Step 1—Tert-ButylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-[2-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]ethoxy]ethyl]carbamate

To a solution of2-[2-[tert-butoxycarbonyl-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]amino]ethoxy]ethylmethanesulfonate (200 mg, 236 umol, Intermediate PI) and3-[5-(aminomethyl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione(160 mg, 492 umol, HCl, Intermediate PH) in ACN (10 mL) was added KI(39.2 mg, 236 umol) and NaHCO₃ (59.5 mg, 709 umol). The reaction mixturewas stirred at 25° C. for 48 hours. On completion, the reaction mixturewas diluted with ACN (100 mL) and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by reversed-phaseflash chromatography (FA, 0.10%) to give the title compound (60.0 mg,24% yield) as a white solid. LC-MS (ESI⁺) m/z 1038.6 (M+H)⁺.

Step2-2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-[2-[2-[[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]methylamino]ethoxy]ethyl]carbamate(50.0 mg, 48.1 umol) in DCM (2 mL) was added HCl/dioxane (4 M, 10 mL).The reaction mixture was stirred at 25° C. for 1 hour. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.05% HCl)-ACN]; B %: 9%-29%, 10 min) to give the title compound(6.50 mg, 14% yield, HCl) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.12 (s, 1H), 10.16 (s, 1H), 9.50 (s, 2H), 9.37 (s, 2H), 9.12 (s, 1H),8.88 (s, 1H), 8.16-8.06 (m, 1H), 7.98-7.88 (m, 2H), 7.78 (d, J=6.8 Hz,2H), 7.54 (s, 1H), 7.36-7.12 (m, 4H), 5.47-5.32 (m, 1H), 4.27-4.22 (m,2H), 3.73 (s, 3H), 3.30-3.23 (m, 6H), 3.16-3.06 (m, 4H), 2.97-2.83 (m,1H), 2.62-2.58 (m, 2H), 2.04-1.90 (m, 1H), 1.18-1.07 (s, 1H), 0.62-0.48(m, 2H), 0.36-0.25 (m, 2H); LC-MS (ESI⁺) m/z 838.4 (M+H).

Example 680:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]ethoxy]ethylamino]methyl]phenylpyrazol-4-yl]oxazole-4-carboxamide,I-685

Step 1—Tert-ButylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-[2-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]ethoxy]ethyl]carbamate

To a solution of3-(3-methyl-2-oxo-5-piperazin-1-yl-benzimidazol-1-yl)piperidine-2,6-dione(50.0 mg, 146 umol, Intermediate PN),2-[2-[tert-butoxycarbonyl-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]amino]ethoxy]ethylmethanesulfonate (148 mg, 175 umol, Intermediate PI) in CH₃CN (8 mL) wasadded NaHCO₃ (36.7 mg, 437 umol), and then the mixture was stirred at80° C. for 6 hrs under N₂ atmosphere. On completion, the mixture wasconcentrated in vacuo, and the residue was purified by reversed-phaseHPLC (0.1% FA condition) to give the title compound (30.0 mg, 15% yield)as a yellow solid. LC-MS (ESI⁺) m/z 1093.6 (M+H)⁺.

Step2-2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]ethoxy]ethylamino]methyl]phenylpyrazol-4-yl]oxazole-4-carboxamide

To a solution of tert-butylN-[[4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]phenyl]methyl]-N-[2-[2-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperazin-1-yl]ethoxy]ethyl]carbamate(20.0 mg, 18.3 umol) in DCM (2 mL) was added TFA (1.54 g, 13.5 mmol,1.00 mL). The mixture was stirred at 15° C. for 0.5 hr. The mixture wasthen concentrated in vacuo, and the residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B3%: 1%-31%, 10 min) to give the title compound (13.6mg, 83% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.96-11.11 (m, 2H), 9.01 (s, 1H), 8.91 (s, 1H), 8.23-8.34 (m, 3H), 8.04(s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.65-7.77 (m, 2H), 7.51 (d, J=8.4 Hz,2H), 7.27 (s, 1H), 7.14-7.21 (m, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.80 (d,J=1.6 Hz, 1H), 6.60 (dd, J=8.4, 2.20 Hz, 1H), 5.26 (dd, J=13.2 Hz, 1H),4.23-4.30 (m, 2H), 3.81 (s, 2H), 3.55 (s, 4H), 3.29 (s, 3H), 3.06 (m,4H), 2.83-2.91 (m, 1H), 2.70 (m, 2H), 2.67-2.69 (m, 2H), 2.61-2.65 (m,2H), 2.58 (m, 4H), 2.07 (s, 3H), 1.96-2.01 (m, 1H), LC-MS (ESI⁺) m/z893.5 (M+H)⁺.

Example 683:N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]ethoxy]ethyl]-6-(1-hydroxy-1-methyl-ethyl)indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide,I-688

A mixture ofN-[6-(1-hydroxy-1-methyl-ethyl)-2-[2-(2-prop-2-ynoxyethoxy)ethyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide(300 mg, 611 umol, Intermediate TK),3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (130mg, 384umol, Intermediate HP), CuI (15.0 mg, 78.7 umol), Pd(PPh₃)₂Cl₂(54.0 mg, 76.9 umol), Cs₂CO₃ (630 mg, 1.93 mmol) and 4 Å molecularsieves (100 mg) in DMF (4 mL) was stirred at 80° C. for 2 hours underN₂. On completion, the reaction mixture was cooled to 20° C. and thenfiltered. The filter cake was washed with EA (10 mL) and the filtratewas concentrated in vacuo. The residue was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 35%-65%, 10 min) to give the title compound (74.2mg, 25% yield) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.36 (s,1H), 11.12 (s, 1H), 8.72 (m, 1H), 8.44 (d, J=8.0 Hz, 1H), 8.37 (d, J=7.6Hz, 1H), 8.34 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.15 (d,J=7.6 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 7.00 (t, J=8.0 Hz, 1H), 5.95 (s,1H), 5.41-5.36 (m, 1H), 4.57 (t, J=5.2 Hz, 2H), 4.41 (s, 2H), 3.93 (t,J=5.2 Hz, 2H), 3.65-3.55 (m, 7H), 2.93-2.82 (m, 1H), 2.74-2.68 (m, 1H),2.65-2.57 (m, 1H), 2.06-1.96 (m, 1H), 1.61 (s, 6H); LC-MS (ESI⁺) m/z748.1 (M+H)⁺.

Example 684 & 685:N-[3-carbamoyl-1-[4-[[2-[2-[3-[(1R)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-686 andN-[3-carbamoyl-1-[4-[[2-[2-[3-[(1S)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide,I-690

Step 1—Tert-ButylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[3-[(1S)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate& Tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[3-[(1R)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate

Tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(190 mg, 192 umol, Example 324, I-329) was separated by SFC (column:DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [0.1% DEA,IPA]; B %: 70%-70%, 5.7 min; 100 minmin) to give the title compoundtert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[3-[(1S)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(95 mg, 50% yield) as a white solid and tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[3-[(1R)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(95 mg, 50% yield) as a white solid. LC-MS (ESI⁺) m/z 988.5 (M+H)⁺ forboth isomers.

Step2—N-[3-carbamoyl-1-[4-[[2-[2-[3-[(1R)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[3-[(1R)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(75.0 mg, 75.9 umol) in DCM (1 mL) was added TFA (1.15 g, 10.1 mmol).The reaction mixture was stirred at 25° C. for 0.5 hr. On completion,the reaction mixture was concentrated in vacuo. The crude product waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 16%-43%, 9 min) to give thetitle compound (36.6 mg, 52% yield, ee 81%, FA salt) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 11.01 (s, 1H), 9.02 (s, 1H),8.90 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.89 (d, J=8.8 Hz,2H), 7.76-7.67 (m, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.27 (s, 1H), 7.18 (dd,J=1.2, 5.2 Hz, 1H), 6.99-6.91 (m, 2H), 6.89-6.83 (m, 1H), 5.36 (dd,J=5.2, 12.8 Hz, 1H), 4.32-4.19 (m, 2H), 3.81 (s, 2H), 3.63-3.52 (m,11H), 2.98-2.91 (m, 2H), 2.91-2.83 (m, 1H), 2.72 (t, J=5.6 Hz, 2H),2.69-2.65 (m, 1H), 2.64-2.58 (m, 1H), 2.04-1.95 (m, 1H), 1.87-1.77 (m,2H); LC-MS (ESI⁺) m/z 888.2 (M+H)⁺.

Step3—N-[3-carbamoyl-1-[4-[[2-[2-[3-[(1S)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]-2-[2-(2,2,2-trifluoroethylamino)-4-pyridyl]oxazole-4-carboxamide

To a solution of tert-butylN-[4-[4-[[3-carbamoyl-1-[4-[[2-[2-[3-[(1S)-1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]-N-(2,2,2-trifluoroethyl)carbamate(75.0 mg, 75.9 umol) in DCM (1 mL) was added TFA (1.15 g, 10.1 mmol).The reaction mixture was stirred at 25° C. for 0.5 hr. On completion,the reaction mixture was concentrated in vacuo. The crude product waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 16%-46%, 10 min) to give thetitle compound (38.0 mg, 510% yield, ee value=85%, FA salt) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 11.01 (s, 1H), 9.02(s, 1H), 8.90 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.04 (s, 1H), 7.89 (d,J=8.8 Hz, 2H), 7.76-7.67 (m, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.27 (s, 1H),7.18 (dd, J=1.2, 5.2 Hz, 1H), 6.99-6.91 (m, 2H), 6.89-6.83 (m, 1H), 5.36(dd, J=5.2, 12.8 Hz, 1H), 4.32-4.19 (m, 2H), 3.81 (s, 2H), 3.63-3.52 (m,11H), 2.98-2.91 (m, 2H), 2.91-2.83 (m, 1H), 2.72 (t, J=5.6 Hz, 2H),2.69-2.65 (m, 1H), 2.64-2.58 (m, 1H), 2.04-1.95 (m, 1H), 1.87-1.77 (m,2H); LC-MS (ESI⁺) m/z 888.2 (M+H)⁺.

Example 686:2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[2-[4-[[1-methyl-7-[(4-morpholinocyclohexyl)amino]pyrazolo[4,3-d]pyrimidin-5-yl]amino]pyrazol-1-yl]ethoxy]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione,I-691

To a solution of5-chloro-1-methyl-N-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidin-7-amine(100 mg, 285 umol, Intermediate LK),4-[2-[2-[2-[2-(4-aminopyrazol-1-yl)ethoxy]ethoxy]ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione (220 mg, 427umol, Intermediate UK) in dioxane (6 mL) was added TFA (650 mg, 5.70mmol). The reaction mixture was stirred at 120° C. for 2 hours. Oncompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [water (0.225% FA)-ACN]; B %: 7%-28%, 7 min) to give thetitle compound (26.0 mg, 110% yield) as yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 11.10 (s, 1H), 8.57 (s, 1H), 7.91 (s, 1H), 7.57 (s, 1H),7.57-7.51 (m, 1H), 7.47 (s, 1H), 7.07 (d, J=8.8 Hz, 1H), 7.02 (d, J=6.8Hz, 1H), 6.56 (t, J=5.6 Hz, 1H), 6.45 (d, J=6.8 Hz, 1H), 5.04 (dd,J=5.2, 12.8 Hz, 1H), 4.16 (t, J=5.6 Hz, 2H), 4.13 (s, 3H), 4.07 (d, J8.0 Hz, 1H), 3.72 (t, J=5.6 Hz, 2H), 3.63-3.59 (m, 4H), 3.57-3.49 (m,12H), 2.92-2.81 (m, 1H), 2.62-2.58 (m, 4H), 2.57-2.53 (m, 2H), 2.39-2.35(m, 1H), 2.10-2.06 (m, 2H), 2.03-1.99 (m, 1H), 1.96-1.92 (m, 2H),1.55-1.46 (m, 2H), 1.42-1.32 (m, 2H). LC-MS (ESI⁺) m/z 829.5 (M+H)⁺.

Example 687:2-(2,6-Dioxo-3-piperidyl)-4-[2-[2-[2-[4-[[1-methyl-7-[(4-morpholinocyclohexyl)amino]pyrazolo[4,3-d]pyrimidin-5-yl]amino]pyrazol-1-yl]ethoxy]ethoxy]ethylamino]isoindoline-1,3-dione,I-692

To a solution ofN5-[1-[2-[2-(2-aminoethoxy)ethoxy]ethyl]pyrazol-4-yl]-1-methyl-N7-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidine-5,7-diamine(60.0 mg, 106 umol, HCl, Intermediate UT) and2-(2,6-dioxo-3-piperidyl)-4-fluoro-isoindoline-1,3-dione (29.3 mg, 106umol, Intermediate R) in DMF (2 mL) was added DIPEA (68.6 mg, 530 umol,92.4 uL). The mixture was stirred at 90° C. for 16 hours. On completion,the reaction mixture was concentrated in vacuo. The residue was purifiedby prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[water (0.225% FA)-ACN]; B %: 9%-30%, 7 min) to give the title compound(13.2 mg, 15% yield, FA) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 8.55 (s, 1H), 7.92 (s, 1H), 7.56 (s, 1H), 7.54-7.43 (m,2H), 7.05-6.96 (m, 2H), 6.55 (t, J=5.6 Hz, 1H), 6.43 (d, J=7.6 Hz, 1H),5.04 (dd, J=5.2, 12.8 Hz, 1H), 4.17 (t, J=5.2 Hz, 2H), 4.12 (s, 3H),4.10-4.04 (m, 1H), 3.74 (t, J=5.2 Hz, 2H), 3.57-3.51 (m, 14H), 2.94-2.78(m, 2H), 2.63-2.58 (m, 1H), 2.57-2.54 (m, 1H), 2.28-2.21 (m, 1H),2.13-1.82 (m, 6H), 1.56-1.45 (m, 2H), 1.39-1.29 (m, 2H); LC-MS (ESI⁺)m/z 785.4 (M+H)⁺.

Example 688:(2S,4R)-1-[(2S)-3,3-dimethyl-2-[[2-[2-[2-[2-[2-[[1-methyl-7-[(4-morpholinocyclohexyl)amino]pyrazolo[4,3-d]pyrimidin-5-yl]amino]ethoxy]ethoxy]ethoxy]ethoxy]acetyl]amino]butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide,I-693

To a solution of (2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]acetyl]amino]-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide(30.0 mg, 45.1 umol, Intermediate ME),5-chloro-1-methyl-N-(4-morpholinocyclohexyl)pyrazolo[4,3-d]pyrimidin-7-amine (14.4 mg, 41.0 umol, Intermediate LK)in NMP (2.00 mL) was added TsOH (707 ug, 4.11 umol). The mixture wasstirred at 150° C. for 6 hours under microwave. On completion, themixture was concentrated in vacuo. The mixture was purified by prep-HPLC(column: Phenomenex Gemini 150*25 mm*10 um; mobile phase: [water (0.04%NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 30%-58%, min). The residue wasre-purified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 um;mobile phase: [water (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %: 30%-54%,min) to give the title compound (2.39 mg, 5% yield) as brown solid. ¹HNMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.59 (t, J=5.6 Hz, 1H), 7.49 (s,1H), 7.42 (s, 1H), 7.39 (m, 4H), 6.31 (d, J=8.0 Hz, 1H), 5.96 (t, J 5.6Hz, 1H), 5.16 (d, J=3.2 Hz, 1H), 4.56 (d, J=9.6 Hz, 1H), 4.48-4.38 (m,2H), 4.37-4.32 (m, 1H), 4.29-4.23 (m, 1H), 4.10 (s, 3H), 4.05-3.98 (m,1H), 3.96 (s, 2H), 3.66-3.57 (m, 6H), 3.56-3.48 (m, 14H), 2.49-2.45 (m,6H), 2.44 (s, 3H), 2.26-2.16 (m, 1H), 2.07-1.98 (m, 3H), 1.95-1.83 (m,3H), 1.54-1.40 (m, 2H), 1.34-1.22 (m, 2H), 0.94 (s, 9H), LC-MS (ESI⁺)m/z 978.7 (M+H)⁺.

Example 689:N-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-5-[4-[2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethyl]piperazin-1-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide,I-694

To a mixture of2-[2-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethoxy]ethyl methanesulfonate (70 mg, 144 umol, Intermediate UB) andN-[3-(difluoromethyl)-1-methyl-pyrazol-4-yl]-5-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine-3-carboxamide(59.7 mg, 144 umol, HCl, Intermediate RD) in ACN (3 mL) was added NaHCO₃(36.4 mg, 434 umol) and KI (2.40 mg, 14.4 umol), and the mixture wasstirred at 80° C. for 16 hours. On completion, the reaction mixture wasquenched with water (15 mL), and then extracted with EA (4×20 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a residue. The residue was purified byprep-HPLC (column: Phenomenex luna C18 150*25 10u; mobile phase: [water(0.225% FA)-ACN]) to give the title compound (8.68 mg, 10.7 umol, 7%yield, FA) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H),9.39 (s, 1H), 8.74 (d, J 7.6 Hz, 1H), 8.34 (s, 1H), 8.26 (s, 1H),7.22-6.91 (m, 3H), 6.88-6.74 (m, 2H), 5.32 (dd, J=5.2, 12.8 Hz, 1H),3.87 (s, 3H), 3.84-3.70 (m, 4H), 3.58 (t, J=5.6 Hz, 2H), 3.55-3.50 (m,4H), 3.30 (s, 3H), 2.94-2.82 (m, 1H), 2.74-2.53 (m, 10H), 2.05-1.92 (m,1H), 1.88-1.71 (m, 2H); LC-MS (ESI⁺) m/z 764.1 (M+H)⁺.

Examples 694 and 695:2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-[(3S)-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-699 &2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-[(3R)-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-700

The2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide(50.0 mg, 54.9 umol, FA salt, Example 406, I-411) was separated by SFC(column: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um); mobile phase: [0.1%NH₃H₂O MeOH]; B %: 70%-70%, 13.7 min; 160 min) to give the twoenantiomers. Then the two enantiomers were purified by prep-HPLC(column: Shim-pack C18 150*25*10 um; mobile phase: [water (0.225%FA)-ACN]; B %: 110%-41%) respectively to give2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-[(3S)-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide(3.40 mg, 12% yield, ee value=91%) as a white solid and2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-[(3R)-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide(3.80 mg, 14% yield, ee value=77%) as a white solid. The absoluteconfiguration of the enantiomers was arbitratily assigned.Characterization of2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-[(3S)-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide:¹H NMR (400 MHz, DMSO-d₆) δ 11.22 (s, 1H), 9.99 (s, 1H), 8.97 (s, 1H),8.78 (s, 1H), 8.36 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 7.79 (d, J=8.8 Hz,2H), 7.47 (d, J=8.8 Hz, 2H), 7.42-7.15 (m, 1H), 7.13-7.07 (m, 2H),7.06-6.96 (m, 3H), 6.88-6.82 (m, 1H), 5.33 (d, J=5.2, 12.8 Hz, 1H), 3.73(s, 2H), 3.31 (s, 6H), 3.21-3.16 (m, 3H), 2.97-2.82 (m, 1H), 2.75-2.55(m, 6H), 2.03-1.94 (m, 1H), 1.66-1.57 (m, 2H), 1.55-1.43 (m, 6H),1.11-1.03 (m, 1H), 0.49-0.41 (m, 2H), 0.26-0.19 (m, 2H); LC-MS (ESI⁺)m/z 865.5 (M+H)⁺. Characterization of2-[2-(cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[4-[4-[1-[(3R)-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-5-yl]butoxy]butylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide:¹H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 9.96 (s, 1H), 8.95 (s, 1H),8.76 (s, 1H), 8.35 (s, 1H), 8.14 (d, J=5.2 Hz, 1H), 7.76 (d, J=8.8 Hz,2H), 7.45 (d, J=8.4 Hz, 2H), 7.40-7.12 (m, 1H), 7.11-7.05 (m, 2H),7.04-6.94 (m, 3H), 6.83 (d, J=8.0 Hz, 1H), 5.30 (d, J=5.2, 12.8 Hz, 1H),3.70 (s, 2H), 3.29 (s, 6H), 3.16 (d, J=6.4 Hz, 3H), 2.93-2.81 (m, 1H),2.73-2.55 (m, 6H), 2.02-1.92 (m, 1H), 1.65-1.55 (m, 2H), 1.53-1.40 (m,6H), 1.11-0.99 (m, 1H), 0.47-0.39 (m, 2H), 0.23-0.17 (m, 2H); LC-MS(ESI⁺) m/z 865.5 (M+H)⁺.

Example 696: AlphaLISA Assay to Determine Ternary Complex Formation

The assay mixture contains 100 nM CRBN-DDB1, 100 nM GST-IRAK4, 20 μg/mLNickle Chelate Donor Bead (Perkin Elmer Catalog #AS101D) and 20 μg/mLGSH Acceptor Bead (Perkin Elmer Catalog #AL109C) in a buffer containing50 mM HEPES, pH 7.5, 100 mM NaCl, 0.1% BSA, 2 mM TCEP, 0.05% Tween-20.Various amount of heterobifunctional degrader compounds were titratedinto the assay mixture ranging from 6.26 nM to 12.8 μM (finalconcentration) in a two-fold dilution series. AlphaLISA signals(Excitation 680 nm and emission 615 nM) were recorded on a Perkin ElmerEnVision 2104 Multilabel reader. The raw data was converted to therelative amount of ternary complex formation by normalization to thesignal generated by His-tagged GST protein only. The final data pointswere plotted and the curves were fit using non-linear regression usingGraphPad Prism software.

The ternary complex formation (as a percentage of total IRAK4) mediatedby I-127 is depicted in FIG. 1 . The ternary complex formation (as apercentage of total IRAK4) mediated by I-135 is depicted in FIG. 2 . Theraw data used for generating FIG. 1 is shown in Table 24.

TABLE 24 Raw data used for generating FIG. 1. [I-127] Average % TernaryComplex Standard (M) (N = 2) Deviation 1.28E−05 1.58 0.05 6.40E−06 3.360.1 3.20E−06 6.74 0.53 1.60E−06 12.53 0.89 8.00E−07 17.79 1.04 4.00E−0725.83 1.28 2.00E−07 28.96 0.34 1.00E−07 31.29 0.17 5.00E−08 23.14 1.862.50E−08 12.66 0.05 1.25E−08 5.89 0.59 6.25E−09 2.71 0.19

The raw data used for generating FIG. 2 is shown in Table 25.

TABLE 25 Raw data used for generating FIG. 2. [I-135] Average % TernaryComplex Standard (M) (N = 2 ) Deviation 1.28E−05 0.61 0.1 6.40E−06 0.5 03.20E−06 0.57 0.06 1.60E−06 0.67 0.03 8.00E−07 1.25 0.03 4.00E−07 4.220.18 2.00E−07 6.15 0.68 1.00E−07 4.16 0.05 5.00E−08 2.54 0.32 2.50E−081.05 0.03 1.25E−08 0.76 0.12 6.25E−09 0.55 0.04

Example 697: ABC-DLBCL Cell Viability Assay

The human ABC-DLBCL cell line SU-DHL-2 (MyD88 S222R, from DSMZ) wasmaintained in IMDM media containing 20% fetal bovine serum and 55 μM2-mercaptoethanol. Cells were harvested by centrifugation, resuspendedin fresh media and added to each well of a 384 well plate at 6000cells/well in 30 μL volume. 30 μL of test compound diluted in media wereadded to each well for assay. Final concentration of test compound wasvaried from a high of 10 μM to a low of 0.0015 μM using a 3-fold, 8 stepserial dilution. Final DMSO concentration was 0.2% for all wells in 60μL final volume. Plates containing cells plus test compounds wereincubated for 4 days at 37° C. in an incubator containing 5% CO₂. Cellviability was determined using CellTiter Glo reagent (Promega). Assayplates were equilibrated to room temperature for 10 minutes. CellTiterGlo was prepared according to manufacturer's instructions, 30 μL wasadded to every well of each assay plate and plates were centrifuged for30 seconds at 1000 rpm. Plates were shaken for 1 minute, centrifuged for30 seconds at 1000 rpm and incubated for 10 minutes at room temperatureto stabilize luminescent signal. Luminescent signal per well wasdetermined using a Perkin Elmer Envision plate reader. Data werenormalized to DMSO treatment as 100% viability and 0.5 μM paclitaxeltreatment as 0% viability. Data were plotted in GraphPad Prism aslog(10) of compound concentration vs % Viability and IC₅₀ calculated asthe inflection point of the logistic curve. ABC-DLBCL cell viabilityresults for I-127 are depicted in FIG. 3 .

Example 698: Human PBMC Cytokine Release Assays

Frozen PBMCs were thawed and rested overnight at 37° C., 5% CO₂. Viablecells were plated at 125,000 per well. Cells were pre-incubated withcompounds for 20 hours (degraders) or 1 hour (kinase inhibitors).Following compound incubation, cells were stimulated with 1 μg/mL of theTLR7/8 agonist R848 (Invivogen #tlrl-r848) or 100 ng/mL of the TLR4agonist LPS (Sigma #L2637) for an additional 4 hours. At the end of theassay, supernatants were harvested and TNFα levels were quantified byMeso Scale Discovery immuno assay (#K151A0H). R848 (TLR7/8) activationresults for I-127 are depicted in FIG. 4 . LPS (TLR4) stimulationresults for I-127 are depicted in FIG. 5 .

Example 699: In Vivo Degradation in Sprague Dawley Rats

Male Sprague Dawley rats aged 7-9 weeks (SLAC Laboratory Animal Co.Ltd., Shanghai, China; or SIPPR-B&K Laboratory Animal Co. Ltd.,Shanghai, China) were assessed as to their general health by a member ofthe veterinary staff or other authorized personnel. Animals wereacclimated for at least 3 days (upon arrival at WuXi AppTec) beforebeing placed on study. Animals were group housed during acclimation andindividually housed during the study. The animal room environment wascontrolled (target conditions: temperature 20 to 26° C., relativehumidity 30 to 70%, 12 hours artificial light and 12 hours dark).Temperature and relative humidity were monitored daily. Animals werefasted at least 12 hours prior to the administration. Animals had accessto water ad libitum and had access to Certified Rodent Diet (BeijingKEAO XIELI Feed Co., Ltd. Beijing, P.R. China) ad libitum afterfinishing infusion. The lot number and specifications of each lot usedwas archived at WuXi AppTec. Water was autoclaved before provided to theanimals ad libitum. Periodic analyses of the water was performed and theresults archived at WuXi AppTec. There were no known contaminants in thediet or water that, at the levels of detection, are expected tointerfere with the purpose, conduct or outcome of the study. I-171 wasformulated as a clear solution in 10% DMSO:90% PEG400 at 5 mg/mL (for 5mg/kg), 10 mg/mL (for 10 mg/kg) or 20mg/ml (for 20 mg/kg). Vehiclecontrol received 10% DMSO:90% PEG400. Groups of 5 animals per conditionwere dosed intravenously with 1 mL of I-171 solution or vehicle via thecatheter indwelled in jugular vein following facility SOPs. Final dosingwas 5 mg/kg, 10 mg/kg, 20 mg/kg or vehicle control. Six hours or 24hours after dosing, animals were humanely sacrificed following facilitySOP and spleens were removed and divided in two equal portions.Splenocytes were prepared by physical dissociation of spleen tissue inice cold phosphate buffered saline (PBS) and passing through a 40 μmcell strainer (Corning). After rinsing the strainer, cells werecollected, transferred to complete media (DMEM, Invitrogen 11995) in a15 mL conical tube and centrifuged at 165×g for 5 minutes to collect.Medium was aspirated and cell pellet was resuspended with 4 mL of ACKlysis buffer (Invitrogen A1049201). 2 mL (half the volume) wasimmediately transferred to a new 15 mL conical tube, resulting in 2×15mL conical tubes per spleen half. Cells were incubated in the dark atroom temperature for 10 minutes. 13 mL of complete medium was added toeach tube and cells were collected by centrifugation for 5 minutes at235×g. Media was aspirated without disturbing cell pellets, cells wereresuspended in 1 mL PBS, and cells from same spleen were combined andpassed through 40 μm cell strainer (Corning). Cells were collected bycentrifugation for 5 min at 300×g, PBS was aspirated and cell pelletswere flash frozen and stored at −80° C. IRAK4 and actin (as a loadingcontrol) were quantified in splenocyte samples by HPLC MS/MS usingisotope labeled internal peptide standard. Total protein per splenocytesample was determined by BCAprotein assay. Background signal for IRAK4was determined as the level present in IRAK4 null patient fibroblastsrelative to total protein, and this value was subtracted from allexperimental samples. Ratio of IRAK4 to actin was determined for allsamples. Treated samples were normalized to time matched vehicle treatedcontrol and expressed as percent of control. Data were plotted andanalyzed in GraphPad Prism software package. Unpaired, two tailed ttests P values are reported as noted by asterisks in the legend of FIG.6 .

Example 700: Pharmacokinetics in Sprague Dawley Rats and CD-1 Mice

Pharmacokinetics for I-127, I-172 and I-210 were determined in SpragueDawley rats or CD-1 mice by dosing intravenous (IV), subcutaneous (SC)or per oral (PO) using facility SOPs and sampling plasma at requiredtime points. Species, formulation, route of administration and timepoints samples are listed below for each compound. Compounds wereextracted from plasma, injected on reverse phase HPLC, eluted with agradient from 5% to 95% acetonitrile in water and quantified by massspectrometry with internal standard. Data are expressed in ng compoundper mL of plasma.

I-210

Rat (Sprague Dawley) iv pk @ 3 mg/kg (IVA depicted in FIG. 7 )

Formulation: 5% DMSO and 2% Cremphor in 20% HP-β-CD in saline

TABLE 26 I-210 concentrations dosed iv @ 3 mg/kg Time Concentration(ng/mL) Mean SD CV (h) Rat 1 Rat 2 Rat 3 (ng/mL) (ng/mL) (%)  0 BLOQBLOQ BLOQ NA NA NA  0.0833 671 652 700 674 24  3.58  0.25 396 418 469428 37  8.76  0.5 307 292 312 304 10  3.43  1 236 232 207 225 16  6.98 2 141 159 132 144 14  9.55  4  86.0  77.7  64.5  76.1 10.8 14.3  8 27.5  24.8  20.3  24.2  3.6 15.0 24  0.454  0.545  0.488  0.496  0.046 9.28

TABLE 27 I-210 PK parameters dosed iv @ 3 mg/kg PK parameters Unit Rat 1Rat 2 Rat 3 Mean SD CV(%) Cl_obs mL/min/kg  40.2  41.2  45.7  42.4  2.9 6.95 T_(1/2) h   2.66   2.83   2.88   2.79  0.11  4.05 C₀ ng/ml  873 814  855  848 30  3.57 AUC_(last) h*ng/ml 1243 1210 1091 1181 80  6.74AUC_(Inf) h*ng/ml 1245 1212 1094 1183 80  6.73 AUC__(%Extrap)_obs %  0.140   0.183   0.185   0.169  0.026 15.1 MRT_(Inf) _bs h   3.26  3.15   2.92   3.11  0.17  5.57 AUC_(last)/D h*mg/mL  414  403  364 394 27  6.74 V_(ss)_obs L/kg   7.85   7.79   8.00   7.88  0.11  1.38

I-210

Rat (Sprague Dawley) po pk @ 10 mg/kg (PO depicted in FIG. 7 )

Formulation: 0.5 CMC and 0.25%˜ Tween 80 in water

TABLE 28 Rat po pk @ 10 mg/kg for I-210 Time Concentration (ng/ml) MeanSD CV (h) Rat 4 Rat 5 Rat 6 (ng/mL) (ng/mL) (%)  0 BLOQ BLOQ BLOQ NA NANA  0.25 0.716 0.359 0.300 0.458 0.225 49.1  0.5 0.914 0.366 0.377 0.5520.313 56.7  1 1.39 0.438 0.426 0.75 0.55 73.6  2 1.55 2.39 0.737 1.560.83 53.0  4 3.50 4.02 1.20 2.91 1.50 51.6  8 1.66 2.46 0.710 1.61 0.8854.4 24 BLOQ BLOQ BLOQ NA NA NA

TABLE 29 Rat PK parameters dosed po @ 10 mg/kg for I-210 PK parametersUnit Rat 1 Rat 2 Rat 3 Mean SD CV(%) T_(1/2) h  3.72  5.65  5.28  4.88 1.02 21.0 T_(max) h  4  4  4  4.00  0.00  0.00 C_(max) ng/ml  3.50 4.02  1.20  2.91  1.50 51.6 AUC_(last) h*ng/ml 17.7 21.1  6.66 15.2 7.6 49.8 AUC_(Inf) h*ng/ml 26.6 41.2 12.1 26.6 14.5 54.6AUC_%Extrap_Obs % 33.5 48.7 44.8 42.3  7.9 18.7 MRT _(Inf)_obs h  7.2710.2  9.35  8.9  1.5 16.8 AUC_(last)/D h*mg/ml  1.77  2.11  0.666  1.52 0.76 49.8 F %  0.450  0.536  0.169  0.385  0.192 49.8

I-210

Rat (Sprague Dawley) iv pk @ 3 mg/kg (IVB depicted in FIG. 7 )

Formulation: 500 DM50 and 2% Cremphor in 20%0 HP-β-CD in saline

TABLE 30 I-210 brain concentration/time data for I-210 Time DetectedConc. (ng/ml) Actual Conc. (ng/g) Mean (h) Group 1 Group 2 Group 1 Group2 (ng/g) 0.083 17.2 11.8 51.6 35.4 43.5 0.25 13.2 12.9 39.6 38.7 39.2 113.3 17.5 39.9 52.5 46.2 4 14.2 12.4 42.6 37.2 39.9 All of the brainsamples were added with PBS by brain weight (g) to PBS volume (mL) Ratio1:2 for homogenating. The actual concentration (ng/g) is the detectedvalue (ng/mL) multiplied by 3.

I-210

Mouse (CD1) iv pk @ 2 mg/kg (IV depicted in FIG. 8 )

Formulation: 20%˜ DMSO and 10% PEG400 in water for injection

TABLE 31 I-210 concentrations dosed iv @ 2 mg/kg in mouse (CD1) TimeConcentration (ng/mL) Mean SD CV (h) Mouse 1 Mouse 2 Mouse 3 (ng/mL)(ng/mL) (%)  0 BLOQ BLOQ BLOQ NA NA NA  0.0833 579 495 692 589 99 16.8 0.25 364 382 424 390 31  7.89  0.5 306 238 306 283 39 13.9  1 220 164195 193 28 14.5  2  89.3  92.5  90.7  90.8  1.6  1.77  4  32.5  20.2 25.6  26.1  6.2 23.6  8   5.72   4.92   4.93   5.19  0.46  8.84 24 BLOQBLOQ BLOQ NA NA NA

TABLE 32 I-210 PK parameters dosed iv @ 2 mg/kg in mouse (CD1) PKparameters Unit Mouse 1 Mouse 2 Mouse 3 Mean SD CV(%) Cl_obs mL/min/kg 46.7  55.8  47.2  49.9  5.1 10.3 T_(1/2) h  1.52  1.48  1.46  1.49 0.03  2.27 C₀ ng/ml 730 563 884 726 160 22.1 AUC_(last) h*ng/ml 701 586695 661  65  9.79 AUC_(Inf) h*ng/ml 714 597 706 672  65  9.72AUC__(%Extrap)_obs %  1.76  1.76  1.47  1.66  0.17 10.0 MRT_(Inf)_obs h 1.58  1.50  1.41  1.50  0.08  5.52 AUC_(last)/D h*mg/mL 351 293 348 331 32  9.79 V_(ss)_obs L/kg  4.42  5.04  4.00  4.48  0.52 11.7

I-210

Mouse (CD1) po pk @ 30 mg/kg (PO depicted in FIG. 8 )

Formulation: 0.5% CMC and 0.25%˜ Tween 80 in water

TABLE 33 I-210 concentrations dosed po @ 30 mg/kg in mouse (CD1) TimeConcentration (ng/ml) Mean SD CV (h) Mouse 4 Mouse 5 Mouse 6 (ng/mL)(ng/mL) (%)  0 BLOQ BLOQ BLOQ NA NA NA  0.25  55.9  23.7  12.8  30.822.4  72.8  0.5 120  23.0  22.2  55 56 102  1 153  16.9  45.1  72 72 100 2 177  91.1 112 127 45  35.4  4  92.5 143 123 120 25  21.3  8  34.8 17.1  16.4  22.8 10.4  45.8 24 BLOQ BLOQ BLOQ NA NA NA

TABLE 34 I-210 PK parameters dosed po @ 30 mg/kg in mouse (CD1) MouseMouse Mouse PK parameters Unit 4 5 6 Mean SD CV (%) T_(1/2) h 2.59 2.202.00 2.27 0.30 13.3 T_(max) h 2 4 4 3.33 1.15 34.6 C_(max) ng/mL 177 143123 148 27 18.5 AUC_(last) h * ng/mL 786 627 615 676 96 14.1 AUC_(Inf)h * ng/mL 917 681 662 753 142 18.8 AUC_%Extrap_obs % 14.2 7.97 7.15 9.83.9 39.5 MRT_(Inf)_obs h 4.22 4.24 3.97 4.14 0.15 3.65 AUC_(last)/D h *mg/mL 26.2 20.9 20.5 22.5 3.2 14.1 F % 9.09 6.76 6.57 7.47 1.40 18.8

I-210

Mouse (CD1) sc pk @ 30 mg/kg (SC depicted in FIG. 8 )

Formulation: 20%˜ DMSO and 1000 PEG400 in water for injection

TABLE 35 I-210 concentrations dosed sc @ 30 mg/kg in mouse (CD1) TimeConcentration (ng/mL) Mean SD CV (h) Mouse 7 Mouse 8 Mouse 9 (ng/mL)(ng/mL) (%) 0 BLOQ BLOQ BLOQ NA NA NA 0.25 74.8 93.0 70.1 79.3 12.1 15.30.5 88.8 101 66.6 85 17 20.4 1 107 107 76.5 97 18 18.2 2 90.0 115 81.195 18 18.4 4 95.9 91.8 105 98 7 6.92 8 39.6 49.0 42.0 43.5 4.9 11.2 243.62 2.88 2.05 2.85 0.79 27.6

TABLE 36 I-210 PK parameters dosed sc @ 30 mg/kg in mouse (CD1) PKparameters Unit Mouse 7 Mouse 8 Mouse 9 Mean SD CV (%) T_(1/2) h 4.343.98 3.56 3.96 0.39 9.80 T_(max) h 1 2 4 2.33 1.53 65.5 C_(max) ng/mL107 115 105 109 5 4.85 AUC_(last) h * ng/mL 980 1102 973 1018 73 7.15AUC_(Inf) h * ng/mL 1003 1119 983 1035 73 7.08 AUC_%Extrap_obs % 2.261.48 1.07 1.60 0.60 37.7 MRT_(Inf)_obs h 6.06 5.82 5.73 5.87 0.17 2.83AUC_(last)/D h * mg/mL 32.7 36.7 32.4 33.9 2.4 7.15 F % 9.94 11.1 9.7510.3 0.7 7.08

I-127

Mouse (CD1) iv pk @ 2 mg/kg (IV depicted in FIG. 9 )

Formulation: 100% DMSO/40% PEG400/10% cremophor RH40/40% water

TABLE 37 I-127 concentrations dosed iv @ 2 mg/kg in mouse (CD1) IV Time(h) M01 M02 M03 Mean IV SD CV (%) 0.0833 2310 831 738 1293 ± 882 68.20.500 166 58.7 82.1 102 ± 56.4 55.2 1.00 91.0 22.3 35.8 49.7 ± 36.4 73.22.00 51.5 12.7 30.9 31.7 ± 19.4 61.2 4.00 18.6 7.08 10.9 12.2 ± 5.8748.1 6.00 8.13 3.38 4.42 5.31 ± 2.50 47.0 24.0 2.20 BQL BQL ND ± ND ND

TABLE 38 I-127 PK parameters dosed iv @ 2 mg/kg in mouse (CD1) PKParameters M01 M02 M03 Mean IV SD CV (%) Rsq_adj 0.821 0.991 0.997 — ± —— No. points used for 3.00 3.00 3.00 3.00 ± — — T_(1/2) C₀ (ng/mL) 39101412 1145 2155 ± 1525 70.8 T_(1/2) (h) 7.43 2.09 1.43 3.65 ± 3.29 90.2Vd_(ss) (L/kg) 5.73 6.36 6.67 6.25 ± 0.480 7.68 Cl (mL/min/kg) 36.3 116103 84.9 ± 42.6 50.2 T_(last) (h) 24.0 6.00 6.00 ND ± — — AUC_(0-last)(ng · h/mL) 896 278 316 496 ± 346 69.8 AUC_(0-inf) (ng · h/mL) 919 288325 511 ± 354 69.4 MRT_(0-last) (h) 1.79 0.618 0.882 1.10 ± 0.614 56.0MRT_(0-inf) (h) 2.63 0.916 1.08 1.54 ± 0.947 61.3 AUC_(Extra) (%) 2.573.55 2.80 2.97 ± 0.512 17.2 AUMC_(Extra) (%) 33.8 34.9 20.8 29.9 ± 7.8426.2

I-127

Mouse (CD1) po pk @ 30 mg/kg (PO depicted in FIG. 9 )

Formulation: 0.5% MC/0.5% Tween80

TABLE 39 I-127 concentrations dosed po @ 30 mg/kg in mouse (CD1) PO Time(h) M04 M05 M06 Mean PO SD CV (%) 0.500 BQL BQL BQL ND ± ND ND 1.00 BQLBQL BQL ND ± ND ND 2.00 BQL BQL BQL ND ± ND ND 4.00 BQL BQL BQL ND ± NDND 6.00 BQL BQL BQL ND ± ND ND 24.0 BQL BQL BQL ND ± ND ND

TABLE 40 I-127 PK parameters dosed po @ 30 mg/kg in mouse (CD1) PKParameters M04 M05 M06 Mean PO SD CV (%) Rsq_adj ND ND ND — ± — — No.points used ND ND ND ND ± — — for T_(1/2) C_(max) (ng/mL) ND ND ND ND ±ND ND T_(max) (h) ND ND ND ND ± ND ND T_(1/2) (h) ND ND ND ND ± ND NDT_(last) (h) ND ND ND ND ± — — AUC_(0-last) ND ND ND ND ± ND ND (ng ·h/mL) AUC_(0-inf) ND ND ND ND ± ND ND (ng · h/mL) MRT_(0-last) (h) ND NDND ND ± ND ND MRT_(0-inf) (h) ND ND ND ND ± ND ND AUC_(Extra) (%) ND NDND ND ± ND ND AUMC_(Extra) (%) ND ND ND ND ± ND ND Bioavailability — — —ND ± — — (%)^(a)

I-127

Mouse (CD1) sc pk @ 30 mg/kg (SC depicted in FIG. 9 )

Formulation: 0.5% MC/0.5% Tween80

TABLE 41 I-127 concentrations dosed sc @ 30 mg/kg in mouse (CD1) SC Time(h) M07 M08 M09 Mean SC SD CV (%) 0.500 1.29 2.28 1.85 1.81 ± 0.496 27.51.00 1.87 2.51 1.61 2.00 ± 0.463 23.2 2.00 2.21 4.61 1.82 2.88 ± 1.5152.5 4.00 1.01 1.86 1.90 1.59 ± 0.503 31.6 6.00 1.41 2.82 1.18 1.80 ±0.888 49.2 24.0 1.30 1.58 1.26 1.38 ± 0.174 12.6

TABLE 42 I-127 PK parameters dosed sc @ 30 mg/kg in mouse (CD1) PKParameters M04 M05 M06 Mean PO SD CV (%) Rsq_adj ND −0.152 ND — ± — —No. points used for T_(1/2) 0 3.00 0 ND ± — — C_(max) (ng/mL) 2.21 4.611.90 2.91 ± 1.48 51.0 T_(max) (h) 2.00 2.00 4.00 2.67 ± 1.15 43.3T_(1/2) (h) ND 39.2 ND ND ± ND ND T_(las)t (h) 24.0 24.0 24.0 24.0 ± — —AUC_(0-last) (ng · h/mL) 33.0 54.5 31.7 39.8 ± 12.8 32.2 AUC_(0-inf) (ng· h/mL) ND 144 ND ND ± ND ND MRT_(0-last) (h) 11.7 10.9 11.4 11.3 ±0.444 3.92 MRT_(0-inf) (h) ND 54.2 ND ND ± ND ND AUC_(Extra) (%) ND 62.1ND ND ± ND ND AUMC_(Extra) (%) ND 92.4 ND ND ± ND ND Bioavailability(%)^(a) — — — 0.534 ± — —

I-172

Mouse (CD1) iv pk @ 2 mg/kg (IV depicted in FIG. 10 )

Formulation: 1000 DMSO and 2% Cremphor in water

TABLE 43 I-172 concentrations dosed iv @ 2 mg/kg in mouse (CD1) TimeConcentration (ng/mL) Mean SD CV (h) Mouse 1 Mouse 2 Mouse 3 (ng/mL)(ng/mL) (%) 0 BLOQ BLOQ BLOQ NA NA NA 0.0833 4150 2810 3290 3417 67919.9 0.25 444 314 404 387 67 17.2 0.5 130 102 136 123 18 14.8 1 34.331.5 38.2 34.7 3.4 9.71 2 11.5 11.7 14.6 12.6 1.7 13.8 4 9.04 6.56 7.707.77 1.24 16.0 8 2.62 2.07 2.69 2.46 0.34 13.8 24 BLOQ BLOQ 2.55 NA NANA

TABLE 44 I-172 PK parameters dosed iv @ 2 mg/kg in mouse (CD1) PKparameters Unit Mouse 1 Mouse 2 Mouse 3 Mean SD CV (%) Cl_obs mL/min/kg26.2 38.0 31.2 31.8 5.9 18.7 T_(1/2) h 2.71 2.40 2.48 2.53 0.16 6.37 C₀ng/mL 12679 8401 9383 10154 2241 22.1 AUC_(last) h * ng/mL 1263 870 10581064 197 18.5 AUC_(Inf) h * ng/mL 1274 877 1067 1073 198 18.5AUC_%Extrap_obs % 0.805 0.818 0.856 0.826 0.026 3.20 MRT_(Inf)_obs h0.332 0.362 1.13 0.61 0.45 74.2 AUC_(last)/D h * mg/mL 632 435 529 53298 18.5 V_(ss)_obs L/kg 0.522 0.826 2.11 1.15 0.84 73.2

I-172

Mouse (CD1) po pk @ 30 mg/kg

Formulation: 0.5 CMC and 0.25% Tween 80 in water

TABLE 45 I-172 concentrations dosed po @ 30 mg/kg in mouse (CD1) TimeConcentration (ng/mL) Mean SD CV (h) Mouse 4 Mouse 5 Mouse 6 (ng/mL)(ng/mL) (%) 0 BLOQ BLOQ BLOQ NA NA NA 0.25 BLOQ BLOQ BLOQ NA NA NA 0.5BLOQ BLOQ BLOQ NA NA NA 1 BLOQ BLOQ BLOQ NA NA NA 2 BLOQ BLOQ BLOQ NA NANA 4 BLOQ BLOQ BLOQ NA NA NA 8 BLOQ BLOQ BLOQ NA NA NA 24 BLOQ BLOQ BLOQNA NA NA

TABLE 46 I-172 PK parameters dosed po @ 30 mg/kg in mouse (CD1) MouseMouse Mouse PK parameters Unit 4 5 6 Mean SD CV (%) T_(1/2) h NA NA NANA NA NA T_(max) h NA NA NA NA NA NA C_(max) ng/mL NA NA NA NA NA NAAUC_(last) h * ng/mL NA NA NA NA NA NA AUC_(Inf) h * ng/mL NA NA NA NANA NA AUC_%Extrap_obs % NA NA NA NA NA NA MRT_(Inf)_obs h NA NA NA NA NANA AUC_(last)/D h * mg/mL NA NA NA NA NA NA F % NA NA NA NA NA NA

I-172

Mouse (CD1) sc pk @ 30 mg/kg (SC depicted in FIG. 10 )

Formulation: 20% DMSO and 1000 Cremphor in water

TABLE 47 I-172 concentrations dosed sc @ 30 mg/kg in mouse (CD1) TimeConcentration (ng/mL) Mean SD CV (h) Mouse 7 Mouse 8 Mouse 9 (ng/mL)(ng/mL) (%) 0 BLOQ BLOQ BLOQ NA NA NA 0.25 34.6 40.0 54.6 43.1 10.3 24.00.5 71.9 57.6 64.8 64.8 7.2 11.0 1 52.6 63.0 78.7 64.8 13.1 20.3 2 48.046.5 58.0 50.8 6.3 12.3 4 33.3 37.0 41.6 37.3 4.2 11.1 6 16.0 20.7 21.519.4 3.0 15.3 24 5.40 4.74 5.85 5.33 0.56 10.5

TABLE 48 PK parameters dosed sc @ 30 mg/kg in mouse (CD1) PK parametersUnit Mouse 7 Mouse 8 Mouse 9 Mean SD CV (%) T_(1/2) h 8.79 7.34 7.898.00 0.74 9.18 T_(max) h 0.5 1 1 0.833 0.289 34.6 C_(max) ng/mL 71.963.0 78.7 71.2 7.9 11.1 AUC_(last) h * ng/mL 422 472 535 476 56 11.8AUC_(Inf) h * ng/mL 491 522 601 538 57 10.6 AUC_%Extrap_obs % 14.0 9.6011.1 11.5 2.2 19.2 MRT_(Inf)_obs h 10.4 8.61 9.13 9.4 0.9 9.84AUC_(last)/D h * mg/mL 14.1 15.7 17.8 15.9 1.9 11.8 F % 3.05 3.25 3.743.34 0.35 10.6

Example 701: Synthesis of2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-210

Step 1—Methyl 4-(3-formyl-1H-pyrazol-1-yl)benzoate (210.3

To a solution of 1H-pyrazole-3-carbaldehyde (10.0 g, 104 mmol, CAS:3920-20-1) and (4-methoxy carbonyl-phenyl) boronic acid (22.5 g, 125mmol, CAS: 99768-12-4) in DCM (50 mL) was added Cu(OAc)₂ (22.7 g, 125mmol) and pyridine (32.9 g, 416 mmol). The reaction mixture was stirredat 25° C. for 18 hours under O₂. On completion, the mixture wasconcentrated in vacuo. The residue was purified by silica gelchromatography to give the title compound (12.0 g, 50% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 10.10 (s, 1H), 8.24-8.14 (m, 2H), 8.06(d, J=2.4 Hz, 1H), 7.90-7.82 (m, 2H), 7.02 (d, J=2.4 Hz, 1H), 3.95 (s,3H).

Step 2—Methyl 4-(4-bromo-3-formyl-1H-pyrazol-1-yl)benzoate (210.4)

To a solution of methyl 4-(3-formylpyrazol-1-yl)benzoate (4.00 g, 17.4mmol) in DMF (40 mL) was added NBS (6.18 g, 34.8 mmol). The reactionmixture was stirred at 25° C. for 1 hour. Then, the reaction mixture washeated to 50° C. for 12 hours. On completion, the mixture wasconcentrated in vacuo. The residue was purified by prep-HPLC (0.1% FAcondition) to give the title compound (4.50 g, 82% yield) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 10.02 (s, 1H), 8.12 (d, J=8.4 Hz, 2H)8.04 (s, 1H), 7.75 (d, J=8.4 Hz, 2H), 3.89 (s, 3H); LC-MS (ESI⁺) m/z310.9 (M+3)⁺.

Step 3—Methyl 4-(4-bromo-3-(difluoromethyl)-1H-pyrazol-1-yl)benzoate(210.5)

To a solution of methyl 4-(4-bromo-3-formyl-pyrazol-1-yl)benzoate (1.70g, 5.50 mmol) in DCM (100 mL) was added DAST (7.98 g, 49.5 mmol) at 0°C. The reaction mixture was stirred at 25° C. for 5 hours. Oncompletion, the mixture was quenched with methanol (30 mL) at 0° C.After that, the mixture was concentrated in vacuo. The residue waspurified by prep-HPLC (0.1% HCl condition) to give the title compound(1.44 g, 78% yield) as a white solid. ¹H NMR (400 MHz, CDCl3) δ 8.17 (d,J=8.8 Hz, 2H), 8.07 (s, 1H), 7.76 (d, J=8.8 Hz, 2H), 6.80 (t, J=53.2 Hz,1H), 3.96 (s, 3H); LC-MS (ESI⁺) m/z 330.9 (M+H)⁺.

Step 4—Methyl4-[4-(benzhydrylideneamino)-3-(difluoromethyl)pyrazol-1-yl]benzoate(210.7)

To a mixture of methyl4-[4-bromo-3-(difluoromethyl)pyrazol-1-yl]benzoate (0.15 g, 453 umol)and diphenylmethanimine (205 mg, 1.13 mmol) in dioxane (3 mL) was addedPd(OAc)₂ (20.8 mg, 92.4 umol), Xantphos (26.2 mg, 45.3 umol) and Cs₂CO₃(448 mg, 1.38 mmol). The mixture was degassed and purged with N₂ for 3times. Then the mixture was stirred at 120° C. for 3 hr under N₂atmosphere. On completion, the mixture was concentrated, then was addedH₂O (30 mL), extracted with EtOAc (3×30 mL). The organic phase was driedwith Na₂SO₄, filtrated and concentrated in vacuo. The residue waspurified by flash silica gel chromatography to give the title compound(0.24 g, 50% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.02-7.95 (m, 2H), 7.80-7.73 (m, 2H), 7.51-7.45 (m, 3H), 7.43-7.31 (m,5H), 7.22-7.19 (m, 2H), 7.12-6.82 (m, 1H), 6.37 (s, 1H), 3.85 (s, 3H);LC-MS (ESI⁺) m/z 432.1 (M+H)⁺.

Step 5—Methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate (210.8)

To a solution of methyl4-[4-(benzhydrylideneamino)-3-(difluoromethyl)pyrazol-1-yl]benzoate (215mg, 498 umol) in THF (2 mL) and MeOH (20 mL) was added HCl/MeOH (4 M,124 uL). The mixture was stirred at 25° C. for 30 minutes. Oncompletion, the mixture was concentrated to give the title compound(0.20 g, 90% yield) as a yellow solid. The crude product was used fornext without purification. LC-MS (ESI⁺) m/z 268.1 (M+H)⁺.

Step 6—Methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate(210.10)

A mixture of methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]benzoate(340 mg, 1.27 mmol),2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carboxylicacid (412 mg, 1.15 mmol), HATU (484 mg, 1.27 mmol), DIEA (411 mg, 3.18mmol, 554 uL) in DMF (10 mL) was degassed and purged with N₂ for 3times, and then the mixture was stirred at 25° C. for 6 hrs. Oncompletion, the mixture was poured into 50 mL H₂O and then filtered togive the residue. The solid was dried in vacuo to give the titlecompound (260 mg, 27% yield) as a yellow solid. LC-MS (ESI⁺) m/z 609.2(M+H)⁺.

Step7-4-[4-[[2-[2-(Cyclopropylmethylamino)-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoic Acid (210.11)

To a solution of methyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate (200mg, 329 umol) in THF (5 mL) and H₂O (5 mL) and MeOH (1 mL) was addedLiOH (39.4 mg, 1.64 mmol). The mixture was stirred at 25° C. for 6 hrs.On completion, the mixture was concentrated, the residue was dilutedwith H₂O (50 mL) and added 1M HCl to adjust pH=5-6, extracted with EA(3×30 mL). The combined organic layers were washed with brine (50 mL),dried over Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (0.13 g, 95% yield) as a yellow solid. LC-MS (ESI⁺) m/z 595.4(M+H)⁺.

Step 8—Isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate(210.13)

To a solution of4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoicacid (250 mg, 420 umol) in THF (10 mL) was added TEA (170 mg, 1.68 mmol)and isopropyl carbonochloridate (128 mg, 1.05 mmol). The mixture wasstirred at −10° C. for 1 hour. On completion, the mixture was filteredand the filtrate was concentrated in vacuo to give the title compound(280 mg, 90% yield) as yellow solid. LC-MS (ESI⁺) m/z 681.3 (M+H)⁺.

Step 9—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(210.14)

To a solution of isopropoxycarbonyl4-[4-[[2-[2-[tert-butoxycarbonyl(cyclopropylmethyl)amino]-4-pyridyl]oxazole-4-carbonyl]amino]-3-(difluoromethyl)pyrazol-1-yl]benzoate (280 mg, 411 umol) in THF(30.0 mL) and H₂O (4.00 mL) was added NaBH₄ (62.2 mg, 1.65 mmol). Themixture was stirred at 0° C. for 1 hour. On completion, the mixture wasdiluted with H₂O (50 mL) extracted with EtOAc (3×30 mL). The organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The mixture was triturated with DCM:PE=1:5 (30 mL), filtered. Thefilter cake was dried in vacuo to give the title compound (200 mg, 83%yield) as white solid. LC-MS (ESI⁺) m/z 581.3 (M+H)⁺.

Step 10—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(210.15)

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-(hydroxymethyl)phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (140 mg,241 umol) in DCM (10.0 mL) was added DMP (204 mg, 482 umol). The mixturewas stirred at 15° C. for 2 hours. On completion, the mixture wasdiluted with DCM (30 mL), extracted with saturated Na₂S₂O₃ (2×30 mL) andsaturated NaHCO₃ (2×30 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to give the title compound(80.0 mg, 57% yield) as white solid. LC-MS (ESI⁺) m/z 579.1 (M+H)⁺.

Step 11—Tert-ButylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(210.16)

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-(4-formylphenyl)pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate (150 mg, 259umol) and 4-[2-[2-(2-aminoethoxy)ethoxy]ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline-1,3-dione(137 mg, 311 umol, HCl, Intermediate ZY) in DCM (10.0 mL) and THF (10.0mL) was added KOAc (76.3 mg, 777 umol) and NaBH(OAc)3 (164 mg, 777umol). The mixture was stirred at 15° C. for 6 hours. On completion, thereaction mixture was quenched by 10 mL H₂O, and extracted with EA (3×10mL). The combined organic layers were washed with brine (20 mL), driedover Na2SO4, filtered and concentrated in vacuo. The residue waspurified by reverse phase (HCl condition H₂O: ACN 0-100%) to give thetitle compound (150 mg, 59% yield) as yellow solid. LC-MS (ESI⁺) m/z967.6 (M+H)⁺.

Step12-2-[2-(Cyclopropylmethylamino)-4-pyridyl]-N-[3-(difluoromethyl)-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]oxazole-4-carboxamide,I-210

To a solution of tert-butylN-(cyclopropylmethyl)-N-[4-[4-[[3-(difluoromethyl)-1-[4-[[2-[2-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethoxy]ethoxy]ethylamino]methyl]phenyl]pyrazol-4-yl]carbamoyl]oxazol-2-yl]-2-pyridyl]carbamate(150 mg, 155 umol) in DCM (2.00 mL) was added HCl/dioxane (4 M, 2.00mL). The mixture was stirred at 15° C. for 0.5 hour. On completion, themixture was concentrated in vacuo. The mixture was purified by prep-HPLC(column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water(0.225% FA)-ACN]; B %: 13%-37%, 10 min) to give the title compound (85.1mg, 60% yield, FA) as yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 11.07(s, 1H), 9.97 (s, 1H), 8.96 (s, 1H), 8.77 (s, 1H), 8.19 (s, 1H), 8.15(d, J=5.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.58-7.72 (m, 1H), 7.47 (d,J=8.8 Hz, 2H), 7.42-7.14 (m, 1H), 7.13-7.10 (m, 2H), 7.10-7.05 (m, 1H),7.04-7.00 (m, 2H), 6.62-6.55 (m, 1H), 5.07-5.00 (m, 1H), 3.79 (s, 2H),3.61-3.51 (m, 8H), 3.46-3.43 (m, 2H), 3.20-3.15 (m, 2H), 2.90-2.82 (m,1H), 2.72-2.67 (m, 2H), 2.61-2.56 (m, 1H), 2.55-2.53 (m, 1H), 2.04-1.96(m, 1H), 1.10-1.01 (m, 1H), 0.48-0.41 (m, 2H), 0.24-0.19 (m, 2H), LC-MS(ESI⁺) m/z 867.1 (M+H)⁺.

While we have described a number of embodiments of this invention, it isapparent that our basic examples may be altered to provide otherembodiments that utilize the compounds and methods of this invention.Therefore, it will be appreciated that the scope of this invention is tobe defined by the appended claims rather than by the specificembodiments that have been represented by way of example.

1-22. (canceled)
 23. A compound of formula I-xxx-1:

or a pharmaceutically acceptable salt thereof, wherein: (a) X and X′ areeach independently CR⁸, N or —N⁺—O⁻; Y is independently N,-N⁺-O⁻ orCR^(8′); provided that at least one of X, X′ or Y is neither N nor—N⁺—O⁻ and that no more than one of X, X′ or Y is —N⁺—O⁻; R¹ isC₁-C₆alkyl; C₂-C₆alkenyl; C₂-C₆alkynyl; —(CR^(3a)R^(3b))_(m)-(3- to7-membered cycloalkyl); —(CR^(3a)R^(3b))_(m)-(3- to 7-memberedheterocycloalkyl) having one to three heteroatoms;—(CR^(3a)R^(3b))_(m)-(5- to 10-membered heteroaryl), having one to threeheteroatoms; or —(CR^(3a)R^(3b))_(m)-C₆-C₁₂aryl; wherein said alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl isoptionally substituted with one to five halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R¹¹, cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or —C₁-C₆alkoxy; R² is—(CR^(3a)R^(3b))_(m)-(3- to 10-membered cycloalkyl);—(CR^(3a)R^(3b))_(m)-(3- to 10-membered heterocycloalkyl) having one tothree heteroatoms; —(CR^(3a)R^(3b))_(m)-(5- to 10 membered heteroaryl)having one to three heteroatoms; or —(CR^(3a)R^(3b))_(m)-C₆-C₁₂aryl;wherein said cycloalkyl, heterocycloalkyl, heteroaryl or aryl isoptionally substituted with one to five R⁴; and wherein, if theheteroatom on said heterocycloalkyl and heteroaryl is N, said N isoptionally substituted with R^(4′); or R² is C₁-C₆alkyl, wherein saidalkyl is optionally substituted with NH₂, OH or cyano; R^(3a) and R^(3b)for each occurrence are independently hydrogen or C₁-C₃alkyl; R⁴ foreach occurrence is independently a bond, deuterium halogen, cyano,C₁-C₆alkyl, C₂-C₆alkenyl, oxo, —OR⁵, —SR⁵, —S(O)R⁹, —S(O)₂R⁹,—NR^(11a)R^(11b), —C(O)R¹⁰—(CR^(3a)R^(3b))_(n)-(3- to 7-memberedcycloalkyl), —(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl),having one to three heteroatoms, —(CR^(3a)R^(3b))_(n)-(5- to 10 memberedheteroaryl), having one to three heteroatoms, or—(CR^(3a)R^(3b))_(n)—C₆-C₁₂ aryl wherein said alkyl, cycloalkyl,heterocycloalkyl, heteroaryl or aryl is each optionally andindependently substituted with one to five deuterium, halogen, OR⁵,—SR⁵, —NR^(11a)R¹¹, cyano, C₁-C₆alkyl, C₃-C₆cycloalkyl or -C1-C₆alkoxy;or two R⁴ taken together with the respective carbons to which each arebonded form a 3- to 6-membered cycloalkyl or 4- to 6-memberedheterocycloalkyl, wherein said cycloalkyl or heterocycloalkyl isoptionally substituted with one to three halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R^(11b), cyano or C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkylor alkoxy is optionally substituted with halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R^(11b), or cyano; and wherein, if a heteroatom on saidheterocycloalkyl is N, said N is optionally substituted with R^(4′);R^(4′) is independently C₁-C₆alkyl, C₂-C₆alkenyl, —C(O)R¹⁰, —S(O)₂R⁹,—(CR^(3a)R^(3b))_(n)-(3- to 7-membered cycloalkyl),—(CR^(3a)R^(3b))_(n)-(4- to 10-membered heterocycloalkyl) orC(O)(CH₂)_(t)CN; wherein said alkyl, alkenyl, cycloalkyl, orheterocycloalkyl is each optionally and independently substituted withone to five deuterium, halogen, OH, cyano or C₁-C₆alkoxy; or R⁴ andR^(4′) taken together with the respective atoms to which each are bondedform a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl,wherein said cycloalkyl or heterocycloalkyl is optionally substitutedwith one to three halogen, deuterium, —OR⁵, —SR⁵, —NR^(11a)R^(11b),cyano, C₁-C₆alkyl or C₁-C₆alkoxy, wherein the alkyl or alkoxy isoptionally substituted with halogen, deuterium, —OR⁵, —SR⁵,—NR^(11a)R^(11b), or cyano; R⁵ is independently hydrogen or C₁-C₆alkyl,wherein said alkyl is optionally substituted with halogen, deuterium,C₁-C₆alkoxy, C₁-C₆alkylthiolyl, —NR^(11a)R^(11b), cyano, C₁-C₆alkyl orC₃-C₆cycloalkyl; or two R taken together with the oxygen atoms to whichthey are bonded form a 5- or 6-membered heterocycloalkyl; R⁶ is—C(O)NHR⁷, CO₂R7 or cyano; R⁷ is hydrogen or C₁-C₆alkyl; each R⁸ isindependently hydrogen, halogen, cyano, —OR⁵, —SR⁵, —NR^(11a)R^(11b),C₆alkyl, C₃-C₆cycloalkyl, 3- to 10-membered heterocycloalkyl or 5- to6-membered heteroaryl or aryl, wherein said alkyl, cycloalkyl,heterocycloalkyl, heteroaryl or aryl is optionally substituted with oneto three halogen, —NR^(11a)R^(11b), OR⁵, —SR⁵, cyano, C₁-C₃ alkyl,—C(O)R¹⁰ or oxo; R^(8′) is hydrogen, deuterium, halogen, cyano, —OR⁵,—SR⁵ or NR^(11a)R^(11b); R⁹ is —(CR^(3a)R^(3b))_(p)-(C₁-C₃alkyl),—(CR^(3a)R^(3b))_(p)-(4- to 6-membered cycloalkyl),—(CR^(3a)R^(3b))_(p)-(4- to 6-membered heterocycloalkyl) or—(CR^(3a)R^(3b))_(p)-(C₅-C₉aryl), wherein said alkyl, cycloalkyl,heterocycloalkyl or aryl are each optionally substituted with fluoro orC₁-C₃alkyl; R¹⁰ is C₁-C₆alkyl, wherein said alkyl is optionallysubstituted with deuterium, halogen, OH, C₁-C₆alkoxy or cyano; R^(11a)and R^(11b) are each independently hydrogen or C₁-C₆alkyl, wherein saidalkyl is optionally substituted with deuterium, C₁-C₆alkoxy or cyano;and if C₂-C₆alkyl, said alkyl is optionally substituted with deuterium,C₁-C₆alkoxy, cyano, halogen or OH; m is independently 0, 1, 2 or 3; n isindependently 0, 1, 2 or 3; p is independently 0 or 1; and t is 1,2 or3; (b) L is a covalent bond or a bivalent, saturated or unsaturated,straight or branched C₁₋₅₀ hydrocarbon chain, wherein 0-6 methyleneunits of L are independently replaced by -Cy-, —O—, —NR—, —S—, —OC(O)—,—C(O)O—, —C(O)—, —S(O)—, —S(O)₂—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—,—C(O)NR—, —OC(O)NR—, —NRC(O)O—,

wherein: each -Cy- is independently an optionally substituted bivalentring selected from phenylenyl, an 8-10 membered bicyclic arylenyl, a 4-7membered saturated or partially unsaturated carbocyclylenyl, a 4-7membered saturated or partially unsaturated spiro carbocyclylenyl, an8-10 membered bicyclic saturated or partially unsaturatedcarbocyclylenyl, a 4-7 membered saturated or partially unsaturatedheterocyclylenyl having 1-2 heteroatoms independently selected fromnitrogen, oxygen, and sulfur, a 4-7 membered saturated or partiallyunsaturated spiro heterocyclylenyl having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, an 8-10 membered bicyclicsaturated or partially unsaturated heterocyclylenyl having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur, a5-6 membered heteroarylenyl having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur, and an 8-10 memberedbicyclic heteroarylenyl having 1-5 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; each of n is independently 1, 2, 3,4, 5, 6, 7, 8, 9, or 10; and each R is independently hydrogen, or anoptionally substituted group selected from C₁₋₆ aliphatic, phenyl, a 4-7membered saturated or partially unsaturated heterocyclic having 1-2heteroatoms independently selected from nitrogen, oxygen, and sulfur,and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur; and (c) LBM is

wherein: X¹ is —C(O)—; X² is —C(O)—; X³ is —CH₂— or —C(O)—; R¹ ishydrogen or C₁₋₄ aliphatic; each of R² is independently hydrogen,halogen, C₁₋₄ aliphatic or —OC₁₋₄ aliphatic; Ring A is a fused ringselected from 6-membered aryl containing 0-1 nitrogen atoms; and m is 0,1, 2, 3 or
 4. 24. The compound of claim 23, wherein X is N, X′ is CR⁸and Y is CR^(8′); X is N, X′ is N and Y is CR^(8′); X is N, X′ is CR⁸and Y is N; X is CR⁸, X′ and Y are N; X and X′ are CR⁸ and Y is N; X isCR⁸ and Y is CR^(8′) and X′ is N; X and X′ are CR⁸ and Y is CR^(8′). 25.The compound of claim 23, wherein R′ is C₁-C₆alkyl.
 26. The compound ofclaim 23, wherein R² is —(CR^(3a)R^(3b))_(m)-(3- to 10-memberedheterocycloalkyl) having one to three heteroatoms; wherein saidheterocycloalkyl is optionally substituted with one to five R⁴.
 27. Thecompound of claim 23, wherein R⁶ is —C(O)NHR⁷ or cyano.
 28. The compoundaccording to claim 23, wherein

wherein

is attached to a modifiable carbon or nitrogen atom.
 29. The compoundaccording to claim 23, wherein


30. The compound according to claim 23, wherein the LBM is selectedfrom:


31. The compound of claim 23, wherein L is a covalent bond or abivalent, saturated or unsaturated, straight or branched C₁₋₂₀hydrocarbon chain, wherein 0-6 methylene units of L are independentlyreplaced by -Cy-, —O—, —NR—, —S—, —OC(O)—, —C(O)O—, —C(O)—, —S(O)—,—S(O)₂—, —NRS(O)₂—, —S(O)₂NR—, —NRC(O)—, —C(O)NR—, —OC(O)NR—, —NRC(O)O—.32. The compound according to claim 23, wherein L is selected from:


33. The compound according to claim 23, wherein said compound isselected from any one of the following compounds, or a pharmaceuticallyacceptable salt thereof.


34. A pharmaceutical composition comprising a compound according toclaim 23, and a pharmaceutically acceptable carrier, adjuvant, orvehicle.
 35. A method of degrading IRAK4 protein kinase in a patient orbiological sample comprising administering to said patient, orcontacting said biological sample with a compound according to claim 23,or a pharmaceutical composition thereof.
 36. A method of treating anIRAK4-mediated disorder, disease, or condition in a patient comprisingadministering to said patient a compound according to claim 23, or apharmaceutical composition thereof.
 37. The method according to claim36, wherein the IRAK4-mediated disorder, disease or condition isselected from a cancer, a neurodegenerative disease, a viral disease, anautoimmune disease, an inflammatory disorder, a hereditary disorder, ahormone-related disease, a metabolic disorder, a condition associatedwith organ transplantation, an immunodeficiency disorder, a destructivebone disorder, a proliferative disorder, an infectious disease, acondition associated with cell death, thrombin-induced plateletaggregation, liver disease, a pathologic immune condition involving Tcell activation, a cardiovascular disorder, and a CNS disorder.
 38. Themethod of claim 36, wherein the IRAK4-mediated disorder, disease orcondition is selected from a MyD88 driven disorder.
 39. The method ofclaim 38, wherein the MyD88 driven disorder is selected from ABC DLBCL,Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneousT-cell lymphoma, and chronic lymphocytic leukemia.